Indazole derivatives

ABSTRACT

The invention is concerned with novel indazole derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds inhibit L-CPT1 and can be used in the prevention or treatment of diseases which are modulated by L-CPT1 inhibitors.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06123321.9, filed Nov. 1, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

The invention is concerned with novel indazole derivatives and their useas inhibitors of liver carnitine palmitoyl transferase 1 (L-CPT1).

High levels of free fatty acids (FFA) lead to an increase of livermitochondrial β-oxidation, which is crucial to drive efficientgluconeogenesis. The mitochondrial oxidation of long-chain FFA requiresthe intervention of two membrane-bound carnitine-dependentpalmitoyltransferases (CPTs). CPT1, the outer mitochondrial membraneenzyme, catalyzes the formation of long-chain acylcarnitines. Liver(L-CPT1) and muscle (M-CPT1) CPT1 isoforms are encoded by two differentgenes and inhibited by malonyl-CoA. The N-ter domain of L-CPT1 confersits lower sensitivity to malonyl CoA. CPT2, the inner mitochondrialmembrane enzyme, reconverts long-chain acylcarnitines into long-chainacyl CoA esters. Long-chain acyl-CoAs are then β-oxidized to acetyl-CoA,which activates the pyruvate carboxylase and gluconeogenesis. Accordingto the mechanism of action described above, pharmaceutically activesubstances which inhibit L-CPT1 reduce liver β-oxidation, consequentlyinhibit gluconeogenesis and therefore counteract hyperglycemia.

SUMMARY OF THE INVENTION

In sum, the present invention relates to the compounds of formula (I):

or a pharmaceutically acceptable salt thereof wherein R¹-R⁶, X, and Y,are as defined in the detailed description and in the claims. Thecompounds of formula I inhibit liver carnitine palmitoyl transferase 1(L-CPT1) activity.

The compounds of the present invention can be used as pharmaceuticallyactive agents which are useful in the prevention and/or treatment ofdiseases which are modulated by L-CPT1 inhibitors, particularly diseaseswhich are related to hyperglycemia and/or glucose tolerance disorders.Such diseases include e.g. diabetes and associated pathologies, noninsulin dependent diabetes mellitus (also referred to as diabetes typeII), obesity, hypertension, insulin resistance syndrome, metabolicsyndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure. Further,the invention is concerned with a process for the manufacture of theabove compounds, pharmaceutical preparations which contain suchcompounds as well as the use of these compounds for the production ofpharmaceutical preparations.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification, the term “lower” is used to mean a groupconsisting of one to seven carbon atoms. In preferred embodiments, alower group has one to four carbon atom(s).

The term “halogen” refers to fluorine, chlorine, bromine or iodine. Inpreferred embodiments, the halogen is fluorine, chlorine or bromine.

The term “alkyl” alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms. In preferred embodiments, thealkyl has one to sixteen carbon atoms, and more preferably one to tencarbon atoms. Lower-alkyl groups as described below also are preferredalkyl groups. Alkyl groups can optionally be substituted with hydroxy,NH₂, N(H,lower-alkyl), N(lower-alkyl)₂ or COOH. Unsubstituted alkylgroups are preferred.

The term “lower-alkyl,” alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto seven carbon atoms. In preferred embodiments, the lower alkyl has oneto four carbon atoms. This term is further exemplified by such radicalsas methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and thelike. Lower-alkyl groups can optionally be substituted with hydroxy,NH₂, N(H, lower-alkyl), N(lower-alkyl)₂ or COOH. Unsubstitutedlower-alkyl groups are preferred.

The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to10 carbon atoms. In preferred embodiments, the cycloalkyl has 3 to 6carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

The term “fluoro-lower-alkyl” refers to lower-alkyl groups which aremono- or multiply substituted with fluorine. Examples offluoro-lower-alkyl groups are, i.e., CFH₂, CF₂H, CF₃, CF₃CH₂, CF₃(CH₂)₂,(CF₃)₂CH and CF₂H—CF₂.

The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ is alower-alkyl.

The term “fluoro-lower-alkoxy” refers to the group R″—O—, wherein R″ isfluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are i.e,CFH₂—O, CF₂H—O, CF₃—O, CF₃CH₂—O, CF₃(CH₂)₂—O, (CF₃)₂CH—O, andCF₂H—CF₂—O.

The term “acid isostere” refers to groups which have similar steric andelectronic features of a carboxylic acid, or that are known in the artto mimic the spatial arrangement and electronic properties of acarboxylic acid. Examples of acid isosteres are 1H-tetrazol-2-yl,4H-[1,2,4]oxadiazol-3-yl-5-one, 4H-[1,2,4]thiadiazol-3-yl-5-one,4H-[1,2,4]oxadiazol-3-yl-5-thione,3H-[1,2,3,5]oxathiadiazol-4-yl-2-oxide, SO₃H, 3-hydroxy-isooxazol,3-hydroxy-pyran-4-one or P(O)(OCH₂CH₃)OH.

The term “aryl”, alone or in combination, relates to the phenyl ornaphthyl group, which can optionally be substituted, unless specificallystated otherwise, by 1 to 5 substituents, independently selected fromthe group consisting of halogen, hydroxy, amino, NO₂, lower-alkyl,hydroxy-lower-alkyl, lower-alkoxy, carboxy, carboxy-lower-alkyl,H₂NC(O), (H,lower-alkyl)NC(O), (lower-alkyl)₂NC(O), fluoro-lower-alkyl,lower-alkyl-SO₂, lower-alkyl-SO₂O, lower-alkyl-SO₂—NH,lower-alkyl-SO₂—N(lower-alkyl), H₂NSO₂, (H, lower-alkyl)NSO₂,(lower-alkyl)₂NSO₂, cyano, heteroaryl, cycloalkyl, phenyl and phenyloxy.In preferred embodiments the aryl is a phenyl group and the number ofsubstituents ranges from 1 to 3. Preferred substituents are halogen,lower-alkyl, fluoro-lower-alkyl, lower-alkoxy and fluoro-lower-alkoxy.Furthermore, the aryl groups can preferably be substituted as describedin the description below.

The term “heteroaryl” refers to an aromatic 5 to 6 membered monocyclicring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3atoms of nitrogen, oxygen or sulphur, such as, i.e., furyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl,oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl,thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoimidazolyl, indolyl,indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl andquinolinyl. Preferred heteroaryl groups are thiophenyl, pyridinyl,furanyl and thiazolyl. Unless specifically stated otherwise, aheteroaryl group may optionally have a substitution pattern as describedearlier in connection with the term “aryl”. Furthermore, heteroarylgroups can preferably be substituted as described in the descriptionbelow.

Compounds of formula (I) can form pharmaceutically acceptable acidaddition salts. Examples of such pharmaceutically acceptable salts aresalts of compounds of formula (I) with physiologically compatiblemineral acids, such as hydrochloric acid, sulphuric acid, sulphurousacid or phosphoric acid. The term “pharmaceutically acceptable salts”refers to such salts. Compounds of formula (I) which comprise an acidgroup such as COOH or an acid isostere can form salts withphysiologically compatible bases. Examples of such salts are alkaline,earth-alkaline and ammonium salts such as e.g. sodium, potassium,calcium and trimethylammonium salt. The term “pharmaceuticallyacceptable salts” also refers to such salts.

The term “pharmaceutically acceptable esters” embraces derivatives ofthe compounds of formula (I), in which a carboxy group has beenconverted to an ester. Lower-alkyl, hydroxy-lower-alkyl,lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- ordi-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl,pyrrolidino-lower-alkyl, piperidino-lower-alkyl, piperazino-lower-alkyl,lower-alkyl-piperazino-lower-alkyl and aralkyl esters are examples ofsuitable esters. The methyl, ethyl, propyl, butyl and benzyl esters arepreferred esters. The term “pharmaceutically acceptable esters”furthermore embraces compounds of formula (I) in which hydroxy groupshave been converted to the corresponding esters with inorganic ororganic acids such as, nitric acid, sulphuric acid, phosphoric acid,citric acid, formic acid, maleic acid, acetic acid, succinic acid,tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and thelike, which are non toxic to living organisms.

In reference to a particular group or molecule, the term “substituted”refers to the fact that at least one of the hydrogen atoms of that groupor molecule is replaced by some other substituent.

The term “a therapeutically effective amount” of a compound means anamount of compound that is effective to prevent, alleviate or amelioratesymptoms of disease or prolong the survival of the subject beingtreated. Determination of a therapeutically effective amount is withinthe skill in the art. The therapeutically effective amount or dosage ofa compound according to this invention can vary within wide limits andmay be determined in a manner known in the art. Such dosage will beadjusted to the individual requirements in each particular caseincluding the specific compound(s) being administered, the route ofadministration, the condition being treated, as well as the patientbeing treated. In general, in the case of oral or parenteraladministration to adult humans weighing approximately 70 Kg, a dailydosage of about 0.1 mg to about 5,000 mg, preferably from about 0.1 mgto about 1,000 mg, more preferably from about 0.5 to 500 mg, and morepreferably from about 1 mg to 300 mg, should be appropriate, althoughthe upper limit may be exceeded when indicated. The daily dosage can beadministered as a single dose or in divided doses, or for parenteraladministration, it may be given as continuous infusion.

The term “pharmaceutically acceptable carrier” is intended to includeany and all material compatible with pharmaceutical administrationincluding solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents, and othermaterials and compounds compatible with pharmaceutical administration.Except insofar as any conventional media or agent is incompatible withthe active compound, use thereof in the compositions of the inventionare contemplated. Supplementary active compounds can also beincorporated into the compositions.

Unless otherwise indicated, the term “a compound of the formula” or “acompound of formula” or “compounds of the formula” or “compounds offormula” means any compound selected from the genus of compounds asdefined by the formula.

In detail, the present invention relates to a compound of formula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein:

X is —C(O)—NH—, —NH—C(O)—, or —(CR⁷R⁸)_(m)—S—, wherein R⁷ and R⁸independently from each other are selected from the group consisting ofhydrogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, andfluoro-lower-alkoxy; and m is 0 or 1; Y is —(CR⁹R¹⁰)_(n)—, wherein R⁹and R¹⁰ independently from each other are selected from the groupconsisting of hydrogen, lower alkyl, fluoro-lower-alkyl, lower-alkoxy,and fluoro-lower-alkoxy; and n is 0 or 1;

R¹, R², R³ and R⁴ independently from each other are selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) lower-alkyl,    -   (4) fluoro-lower-alkyl,    -   (5) lower-alkoxy,    -   (6) fluoro-lower-alkoxy,    -   (7) carbamoyl,    -   (8) lower-alkyl-NH—C(O)—NH,    -   (9) aryl-lower-alkyl-NH—C(O)—NH, and    -   (10) lower-alkyl-SO₂—NH-lower-alkyl;        R⁵ is phenyl or a heteroaryl selected from the group consisting        of (a) thiophenyl, (b) pyridinyl, (c) furanyl, and (d)        thiazolyl, which phenyl or heteroaryl is optionally substituted        with 1 to 3 substituents independently selected from the group        consisting of:    -   (1) halogen,    -   (2) lower-alkyl,    -   (3) fluoro-lower-alkyl,    -   (4) lower-alkoxy,    -   (5) fluoro-lower-alkoxy,    -   (6) hydroxy,    -   (7) HO—SO₂,    -   (8) NH₂—SO₂,    -   (9) N(H,lower-alkyl)-SO₂,    -   (10) N(lower-alkyl)₂-SO₂,    -   (11) lower-alkyl-SO₂—NH,    -   (12) carboxy,    -   (13) carboxy-lower-alkyl,    -   (14) carboxy-lower-alkoxy,    -   (15) NO₂,    -   (16) CN,    -   (17)NH₂,    -   (18) N(H,lower-alkyl),    -   (19) N(lower-alkyl)₂,    -   (20) NH₂C(O),    -   (21) N(H,lower-alkyl)C(O),    -   (22) N(lower-alkyl)₂C(O),    -   (23) lower-alkyl-C(O)NH,    -   (24) 1H-tetrazol-5-yl and    -   (25) 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl;

R⁶ is C₂₋₇-alkyl or

-   -   wherein: (a) R¹¹ and R¹² independently from each other are        selected from the group consisting of hydrogen, lower-alkyl,        fluoro-lower-alkyl, lower-alkoxy, and fluoro-lower-alkoxy; (b)        R¹³, R¹⁴ and R¹⁵ independently from each other are selected from        the group consisting of hydrogen, lower-alkyl, halogen,        fluoro-lower-alkyl, lower-alkoxy, hydroxy, fluoro-lower-alkoxy,        NO₂ or NH₂—C(O); and (c) R¹⁶ is hydrogen or lower-alkoxy;        with the proviso that the compound of formula (I) is not:

-   N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,

-   4-methyl-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,

-   4-nitro-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,

-   4-chloro-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,

-   4-methoxy-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,

-   N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzenacetamide, or

-   N-(1-ethyl-1H-indazol-3-yl)-benzamide.

Compounds of formula (I) are individually preferred and physiologicallyacceptable salts thereof are individually preferred and pharmaceuticallyacceptable esters thereof are individually preferred, with the compoundsof formula (I) being particularly preferred.

N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzenacetamide is also known asN-[1-(phenylmethyl)-1H-indazol-3-yl]-benzeneacetamide.

The compounds of formula (I) can have one or more asymmetric carbon orsulfur atoms and can therefore exist as an enantiomeric mixture, mixtureof stereoisomers or as optically pure compounds.

A preferred embodiment of the present invention relates to compounds offormula (I) as described above, wherein X is —C(O)—NH— or —NH—C(O)—.Compounds in which X is —C(O)—NH— or —NH—C(O)— indivudually constituteseparate preferred embodiments of the present invention.

Other preferred compounds of the present invention are those, whereinR¹, R², R³ and R⁴ independently from each other are hydrogen, halogen,carbamoyl, lower-alkyl-NH—C(O)—NH, aryl-lower-alkyl-NH—C(O)—NH orlower-alkyl-SO₂—NH-lower-alkyl. Preferably, R¹, R², R³ and R⁴independently from each other are hydrogen or halogen. More preferably,R¹ is hydrogen. It is also preferred, that R² is hydrogen. Furthermore,it is preferred that R³ is hydrogen or fluoro. In addition, it ispreferred that R⁴ is hydrogen.

Another preferred embodiment of the present invention is related tocompounds of formula (I) as described above, wherein R⁵ is phenyl orheteroaryl selected from the group consisting of thiophenyl, pyridinyl,furanyl and thiazolyl, which phenyl or heteroaryl is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halogen, lower-alkyl, lower-alkoxy, carboxy,carboxy-lower-alkyl, carboxy-lower-alkoxy, 1H-tetrazol-5-yl and5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl. Phenyl and heteroarylindividually constitute separate preferred embodiments of the presentinvention. More preferably, R⁵ is phenyl or thiophenyl, which phenyl orthiophenyl is optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halogen,lower-alkoxy, carboxy and 1H-tetrazol-5-yl. It is particularly preferredthat R⁵ is 4-carboxy-phenyl, thiophenyl, phenyl, 3-fluoro-phenyl,3-methoxy-phenyl or 4-(1H-tetrazol-5-yl)-phenyl.

Other preferred compounds of the present invention are those, wherein R⁶is

and R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined above.

Preferred compounds of formula (I) as described above are those whereinR⁷ is hydrogen. Other preferred compounds are those, wherein R⁸ ishydrogen. Other preferred compounds are those, wherein R⁹ is hydrogen.It is also preferred that R¹⁰ is hydrogen. Furthermore, it is preferredthat R¹¹ is hydrogen. Compounds in which R¹² is hydrogen are alsopreferred.

In a preferred embodiment of the present invention, R¹³, R¹⁴ and R¹⁵independently from each other are hydrogen, halogen, fluoro-lower-alkyl,lower-alkoxy, fluoro-lower-alkoxy, NO₂ or NH₂—C(O). Preferably, R¹³, R¹⁴and R¹⁵ independently from each other are hydrogen, halogen,fluoro-lower-alkyl, fluoro-lower-alkoxy or NH₂—C(O). More preferably,R¹³ is hydrogen, trifluoromethyl or chloro. It is also preferred thatR¹⁴ is hydrogen, difluoromethoxy or NH₂—C(O). Preferably, R¹⁵ ishydrogen. Furthermore, it is preferred that R¹⁶ is hydrogen.

Other preferred compounds are those, wherein m is 1. Compounds in whichn is 0 or 1, individually constitute separate preferred embodiments ofthe present invention.

In particular, preferred compounds are the compounds of formula (I)described in the examples as individual compounds as well aspharmaceutically acceptable salts as well as pharmaceutically acceptableesters thereof. Furthermore, the substituents as found in the specificexamples described below, individually constitute separate preferredembodiments of the present invention.

Preferred compounds of formula (I) are those selected from the groupconsisting of:

-   N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-terephthalamic    acid,-   N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-benzamide,-   Thiophene-2-carboxylic acid    [1-(4-difluoromethoxy-benzyl)-1H-indazol-3-yl]-amide,-   N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-3-fluoro-benzamide,-   N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-3-methoxy-benzamide,-   N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-isonicotinamide,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic    acid,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide,-   Thiophene-2-carboxylic acid    [1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-isonicotinamide,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-nicotinamide,-   N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic    acid,-   N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide,-   N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide,-   N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide,-   Thiophene-2-carboxylic acid    [1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,-   Furan-2-carboxylic acid    [1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,-   N-[1-(4-Difluoromethoxy-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamic    acid,-   N-[1-(3-Chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamic    acid,-   Thiophene-2-carboxylic acid    [1-(3-chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-amide,-   N-[1-(3-Chloro-benzyl)-6-fluoro-1H-indazol-3-yl]-terephthalamic    acid,-   Thiophene-2-carboxylic acid    [1-(4-difluoromethoxy-benzyl)-6-fluoro-1H-indazol-3-yl]-amide,-   Thiophene-2-carboxylic acid (1-benzyl-1H-indazol-3-yl)-amide,-   1-Ethyl-5-(3-propyl-ureido)-1H-indazole-3-carboxylic acid    (thiophen-2-ylmethyl)-amide,-   1-Ethyl-5-(3-isopropyl-ureido)-1H-indazole-3-carboxylic acid    (thiophen-2-ylmethyl)-amide,-   1-Ethyl-5-(3-phenethyl-ureido)-1H-indazole-3-carboxylic acid    (thiophen-2-ylmethyl)-amide,-   1-Ethyl-5-(3-ethyl-ureido)-1H-indazole-3-carboxylic acid    (thiophen-2-ylmethyl)-amide,-   1-(4-Nitro-benzyl)-1H-indazole-3-carboxylic acid    (pyridin-3-ylmethyl)-amide,-   1-(4-Difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid    (thiophen-2-ylmethyl)-amide,-   1-(3-Trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid    (thiophen-2-ylmethyl)-amide,-   4-({[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-methyl)-benzoic    acid,-   (2-{[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid    [4-(1H-tetrazol-5-yl)-phenyl]-amide,-   1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid    4-(1H-tetrazol-5-yl)-benzylamide,-   (4-{[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-2-methyl-phenoxy)-acetic    acid,-   1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid    [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide,-   4-{[5-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carbonyl]-amino}-benzoic    acid,-   5-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid    [4-(1H-tetrazol-5-yl)-phenyl]-amide,-   5-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid    4-(1H-tetrazol-5-yl)-benzylamide,-   1-(4-Carbamoyl-benzyl)-1H-indazole-3-carboxylic acid    4-(1H-tetrazol-5-yl)-benzylamide,-   1-(4-Carbamoyl-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid    4-(1H-tetrazol-5-yl)-benzylamide,-   1-(5-Chloro-2-methoxy-benzyl)-5-fluoro-3-[4-(1H-tetrazol-5-yl)-phenylsulfanylmethyl]-1H-indazole,-   1-(4-Difluoromethoxy-benzyl)-1H-indazole-3,6-dicarboxylic acid    6-amide 3-[4-(1H-tetrazol-5-yl)-benzylamide], and-   1-(4-Difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylic    acid [4-(1H-tetrazol-5-yl)-phenyl]-amide,    and pharmaceutically acceptable salts and esters thereof.

Particularly preferred compounds of formula (I) are those selected fromthe group consisting of:

-   N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-terephthalamic    acid,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic    acid,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide,-   Thiophene-2-carboxylic acid    [1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,-   N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide,-   N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic    acid,-   Thiophene-2-carboxylic acid    [1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,-   1-(3-Trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid    (thiophen-2-ylmethyl)-amide, and-   1-(4-Carbamoyl-benzyl)-1H-indazole-3-carboxylic acid    4-(1H-tetrazol-5-yl)-benzylamide,    and pharmaceutically acceptable salts and esters thereof.

It will be appreciated that the compounds of general formula (I) in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

The invention further relates to a process for the manufacture ofcompounds of formula (I) as defined above, which process comprisesreacting a compound of formula (VII)

with a compound of formula hal-R⁶, wherein R¹, R², R³, R⁴, R⁵, R⁶, X andY are as defined above, and hal is selected from the group consisting ofchloro, bromo and iodo.

The reaction of a compound of formula (VII) with a compound of formulahal-R⁶ can be carried out under conditions well known to the personskilled in the art. For example, the compound of formula (VII) isreacted with a compound of formula hal-R⁶, e.g. a benzyl halogenidederivative, in a nucleophilic substitution reaction, using methods wellknown to someone skilled in the art. As halogenides, bromides, iodidesor chlorides can be used. The reaction can be carried out at temperaturebetween room temperature and 200° C., optionally under microwaveirradiation, in various solvents, preferably polar aprotic solvents suchas acetone, dimethylformamide, dimethylsulfoxide and the like. A basecan conveniently be added. As bases, both organic and inorganic basescan be used, such as for example potassium tert-butylate, sodiumhydride, potassium carbonate, cesium carbonate or others.

The present invention also relates to compounds of formula (I) asdefined above, when prepared by a process as described above.

The compounds of formula (VII) and hal-R⁶ can be prepared by methodsknown in the art or as described below or in analogy thereto. Unlessotherwise indicated, R¹, R², R³, R⁴, R⁵, R⁶, X and Y are as describedabove.

Compounds of formula I, wherein X is —NH—C(O)— are part of the presentinvention and are represented by general formula II

Compounds of general formula II can be accessed according to thefollowing general scheme 1:

In step 1, scheme 1, a 2-fluorobenzonitrile 1 is reacted with hydrazineto produce a 3-amino-indazole 2, according to methods well known tothose skilled in the art. This involves treating the2-fluorobenzonitrile with hydrazine or hydrazine hydrate at temperaturesbetween 0° C. and 200° C. The reaction can be carried out in the absenceof solvent or in the presence of an alcoholic solvents like ethanol,butanol or other alcoholic solvents.

In step 2, scheme 1, the free amino group of 3-amino-indazole 2 isprotected to the corresponding formamidino derivative 3. This involvesreacting the amino indazole 2 with a formamide equivalent, for examplewith dimethylformamide dimethylacetal, chloromethylene-dimethyl-ammoniumchloride and the like. The reaction is usually carried out withoutsolvent or in an alcoholic solvent, as for example methanol or ethanol,at temperatures between 0° C. and 100° C.

In step 3, scheme 1, the protected 3-amino-indazole 2 is reacted with abenzyl or alkyl halogenide in a nucleophilic substitution reaction,using methods well known to someone skilled in the art. As alkyl orbenzyl halogenides, alkyl- or benzyl-bromides, iodides or chlorides canbe used. The reaction can be carried out at temperature between roomtemperature and 200° C., optionally under microwave irradiation, invarious solvents, preferably polar aprotic solvents such as acetone,dimethylformamide, dimethylsulfoxide and the like. As bases, bothorganic and inorganic bases can be used, such as for example potassiumtert-butylate, sodium hydride, potassium carbonate, cesium carbonate orothers.

In step 4, scheme 1, the formamidine protective group is removed toyield the free 3-aminoindazole 5 according to methods well known tosomeone skilled in the art, for example by treatment with a base likehydrazine hydrate, sodium hydroxide or other in alcoholic solvent atroom temperature.

In step 5, scheme 1, the amino group of 3-aminoindazoles 5 is converted,with the appropriate acid R⁵⁻Y—CO₂H, into the corresponding product ofgeneral formula II, using methods well known to someone skilled in theart e.g. amide formation using a coupling reagent. The reaction istypically carried out in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between 0° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine, and/or4-(dimethylamino)pyridine. Typically used coupling agents areN,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate and bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate. Alternatively, such reaction can be performed bycoupling the amino group of 3-aminoindazoles 5 with an appropriate acylhalide, typically an acyl chloride of general formula R⁵⁻Y—COCl in thepresence of a base. The reaction is generally conducted in an aproticsolvent, like dichloromethane, tetrahydrofuran or acetone, in thepresence of a base. Typical bases are triethylamine, 4-methylmorpholine,pyridine, diisopropylethylamine or 4-(dimethylamino)pyridine or mixturesthereof. Solid phase bound bases, like for example polystyrene boundcarbonate can be used. Occasionally, double acylation of the amino groupof 3-aminoindazoles 5 is observed. In such cases, the diacylated productcan be reconverted to the desired product II by treatment with a base,typically aqueous NaOH, KOH or LiOH. Solid phase bound bases, like forexample solid phase bound diethylenetriamine can also be used.

Compounds of formula I where X is —C(O)—NH— are part of the presentinvention and are represented by general formula III

Compounds of general formula III can be accessed according to thefollowing general scheme 2:

In step 1, scheme 2, indazole-3-carboxylic acids 6 are converted, withthe appropriate amine R⁵—Y—NH₂, into the corresponding amides of generalformula 7, using methods well known to someone skilled in the art, e.g.amide formation using a coupling reagent. The reaction is typicallycarried out in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between 0° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine, and/or4-(dimethylamino)pyridine. Typically used coupling agents areN,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate and bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate. Alternatively, such reaction can be performed intwo steps involving first formation of the acyl halide derivative of 6and subsequent coupling reaction with an appropriate amine in thepresence of a base. Typically employed reagents for the formation of theacyl chloride are thionyl chloride, phosphorous pentachloride, oxalylchloride, (1-chloro-2-methyl-propenyl)-dimethyl-amine or cyanuricchloride, and the reaction is generally conducted in the absence of asolvent or in the presence of an aprotic solvent like dichloromethane,toluene or acetone. A base can optionally be added, like for examplepyridine, triethylamine, diisopropylethylamine or 4-methylmorpholine.The obtained acyl chloride can be isolated or reacted as such with amineR⁵—Y—NH₂ in an aprotic solvent, like dichloromethane, tetrahydrofuran oracetone, in the presence of a base. Typical bases are triethylamine,4-methylmorpholine, pyridine, diisopropylethylamine or4-(dimethylamino)pyridine or mixtures thereof.

In step 2, scheme 2, the indazole-3-carboxylic acid amides are reactedat the free indazole NH with a benzyl or alkyl halogenide in anucleophilic substitution reaction, using methods well known to someoneskilled in the art. As alkyl or benzyl halogenides, alkyl- orbenzyl-bromides, iodides or chlorides can be used. The reaction can becarried out at temperature between room temperature and 200° C.,optionally under microwave irradiation, in various solvents, preferablypolar aprotic solvents such as acetone, dimethylsulfoxide and the like.As bases, both organic and inorganic bases can be used, such as forexample potassium tert-butylate, sodium hydride, potassium carbonate,cesium carbonate or others.

Alternatively, compounds of general formula III can be accessedaccording to the following general scheme 3:

In step 1, scheme 3, the carboxylic acid group of indazole-3-carboxylicacids 6, is protected according to methods well known to someone skilledin the art, e.g. via ester formation. The reaction is performed bytreated the indazole-3-carboxylic acids 6 with an appropriate alcohol inthe presence of a coupling agent. The reaction is typically carried outin aprotic solvents such as dichloromethane, tetrahydrofuran,N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof attemperatures between 0° C. and 80° C. in the presence or absence of abase such as triethylamine, diisopropylethylamine, 4-methylmorpholine,and/or 4-(dimethylamino)pyridine. Typically used coupling agents areN,N′-dicyclohexylcarbodiimide, carbonyldiimidazole,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate and bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate. Alternatively, the reaction can be performed bytreating a mixture of the acid 6 and the desired alcohol with a mineralacid, like for example anhydrous hydrochloric acid or concentratedsulfuric acid. The reaction is typically carried out at temperaturesbetween 0° C. and a 100° C. and the desired alcohol is used as solvent.As alcohols, methanol, ethanol and 2-trimethylsilylethanol can be used.

In step 2, scheme 3, the indazole-3-carboxylic acid esters 8 are reactedat the free indazole NH with a benzyl or alkyl halogenide in anucleophilic substitution reaction, using methods well known to someoneskilled in the art. As alkyl or benzyl halogenides, alkyl- orbenzyl-bromides, iodides or chlorides can be used. The reaction can becarried out at temperature between room temperature and 200° C.,optionally under microwave irradiation, in various solvents, preferablypolar aprotic solvents such as acetone, dimethylsulfoxide and the like.As bases, both organic and inorganic bases can be used, such as forexample potassium tert-butylate, sodium hydride, potassium carbonate,cesium carbonate or others.

In step 3, scheme 3, the indazole-3-carboxylic acid esters 9 areconverted into the corresponding carboxylic acids of the formula 10,using methods well known to someone skilled in the art, e.g. basemediated ester hydrolysis. The reaction is typically carried out insolvents such as water, methanol, ethanol, tetrahydrofuran and mixturesthereof at temperatures between −20° C. and 120° C. Typical reagents areaqueous or anhydrous lithium hydroxide, lithium hydroxide monohydrate,sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodiumcarbonate, potassium hydrogen carbonate and potassium carbonate. In thecase where R is 2-trimethylsilylethyl, the hydrolysis reaction can beperformed using a fluoride source instead than an aqueous base. Thereaction is carried out in an organic solvent, like for exampledichloromethane, tetrahydrofuran, N,N-dimethylformamide, at temperaturesbetween −10° C. and 100° C. Typically used fluoride sources aretetrabutylammonium fluoride, hydrogen fluoride-pyrdine and hydrofluoricacid, as well as others well known to someone skilled in the art.

In step 4, scheme 3, indazole-3-carboxylic acids 10 are converted, withthe appropriate amine R⁵—Y—NH₂, into the corresponding amides of generalformula III, in analogy to what described in scheme 2, step 1.

Compounds of formula I where X is —CH₂—S— are part of the presentinvention and are represented by general formula IV:

Compounds of general formula IV can be accessed according to thefollowing general scheme 4:

In step 1, scheme 4, the already described indazole-3-carboxylic acidesters 9 are converted to the corresponding (indazol-3-yl)-methanolderivatives 11 according to methods well known to someone skilled in theart e.g. via ester reduction. The reaction is typically carried out inan aprotic solvent, as for example tetrahydrofuran, diethyl ether or thelike, at temperatures between −10° C. and 25° C. Typically employedreducing agents are diborane, sodium borohydride, lithium borohydride,diisobutylaluminium hydride, lithium aluminium hydride and others wellknown to someone skilled in the art.

In step 2, scheme 4, the (indazol-3-yl)-methanol derivatives 11 areconverted to the corresponding chlorides 12 according to methods wellknown to someone skilled in the art. The reaction is carried out in theabsence of solvent or in the presence of an aprotic solvent likemethylene chloride, chloroform, carbon tetrachloride and the like.Typically used reagents are phosphorous pentachloride, thionyl chlorideand others well known in the art.

In step 3, scheme 4, the 3-chloromethyl-indazole derivatives 12 areconverted to compounds of general formula IV according to methods wellknown to someone skilled in the art, e.g. nucleophilic substitution withan appropriate thiol derivative R⁵—Y—SH. The reaction is typicallycarried out in a polar aprotic solvent, as for example tetrahydrofuran,acetone, acetonitrile, dimethylformamide, dimethylsulfoxide or the like,at temperatures between −10° C. and 100° C. in the presence of a base.Typically used bases are organic or inorganic bases like for examplepotassium tert-butylate, sodium hydride, potassium carbonate, cesiumcarbonate or others.

The compounds of general formula 6 which are necessary for thepreparation of compounds of general formula II, III and IV can beaccessed according to the following general scheme 5:

In step 1, scheme 5, indole derivatives 13, which are commerciallyavailable, or prepared according to methods well known in the art areconverted to the corresponding 1H-indazole-3-carbaldehydes 14 accordingto the method described in J. Med. Chem. 1997, 2843. This involvestreatment of the indole 13 with aqueous sodium nitrite in acidic medium,for example in aqueous hydrochloric acid.

In step 2, scheme 5, the 1H-indazole-3-carbaldehydes 14 are converted tothe corresponding 1H-indazole-3-carboxylic acids 6 according to methodswell known to someone skilled in the art e.g. aldehyde oxidation. Thereaction can be carried out under a variety of methods and conditions.Typically used reagents are buffered sodium chlorite, acidic potassiumdichromate, hydrogen peroxide, or other adequate oxidizing agents wellknown in the art.

Alternatively, 1H-indazole-3-carboxylic acids 6 are prepared directlyfrom isatines 15 according to the multistep methodology described in J.Am. Chem. Soc. 1952, 2009. This involves treatment of the isatines 15with an aqueous base, as for example sodium hydroxyde, followed bydiazotization of the free amine with sodium nitrite in acidic medium, asfor example aqueous sulfuric or hydrochloric acid. The diazonium salt isthen reduced with tin(II) chloride in acidic media to the correspondinghydrazine, which cyclizes to form the desired 1H-indazole-3-carboxylicacids 6.

Compounds of formula I where X is —C(O)—NH— and R³ islower-alkyl-NH—C(O)—NH— or aryl-lower-alkyl-NH—C(O)—NH— are part of thepresent invention and are represented by general formula V

Compounds of general formula V can be accessed according to thefollowing general scheme 6:

In step 1, scheme 6, 5-nitro-indazole-3-carboxylic acid amides offormula 16, which can be obtained according to any of the methodsdescribed in the schemes above, are converted to the corresponding5-amino-indazole-3-carboxylic acid amides 17 according to methods wellknown to someone skilled in the art e.g. nitro reduction. The reactionis typically carried out using reducing metals like iron or tin, in asolvent such as methanol, ethanol, acetic acid, water, or mixturesthereof, optionally in the presence of an acid such as ammoniumchloride, hydrochloric acid, or sulfuric acid, at temperatures of20-100° C.

In step 2, scheme 6, the 5-amino-indazole-3-carboxylic acid amides 17are converted to the products of general formula V according to methodswell known to someone skilled in the art e.g. urea formation. Typicallyused reagent is an adequate alkyl or aryl isocyanate. The reaction canbe conducted in an aprotic solvent, like for example dichloromethane,dimethylformamide, acetonitrile and the like, in the presence of a baselike for example triethylamine, diisopropylethylamine,N-methylmorfoline, and the like.

Compounds of formula I where X is —C(O)—NH— and R² islower-alkyl-SO₂—NH-lower-alkyl are part of the present invention and arerepresented by general formula VI

Compounds of general formula VI can be accessed according to thefollowing general scheme 7:

In step 1, scheme 7, 5-cyano-1H-indazole-3-carboxylic acid esters offormula 18, which can be obtained according to any of the methodsdescribed in the schemes above, are converted to the corresponding5-aminomethyl-1H-indazole-3-carboxylic acid esters 19 according tomethods well known to someone skilled in the art e.g. nitrile reduction.The reaction can be carried out by any of the known method to reduce anitrile to amine, like for example catalytic hydrogenation with platinumoxide.

In step 2, scheme 7, the free amino group of5-aminomethyl-1H-indazole-3-carboxylic acid esters 19 is protected witha tert-butoxycarbonyl group, according to methods well known to someoneskilled in the art, e.g. by reacting the amine withdi-tert-butyldicarbonate in the presence of a base, like for exampletriethylamine, diisopropylethylamine or other organic or inorganicbases.

In step 3, scheme 7, the protected5-aminomethyl-1H-indazole-3-carboxylic acid esters 20 are reacted at thefree indazole NH with a benzyl or alkyl halogenide in a nucleophilicsubstitution reaction, in analogy to what described in scheme 3, step 2.

In step 4, scheme 7, the tert-butylcarbamate group of compounds 21 isremoved to give the compounds of formula 22, using methods well known tosomeone skilled in the art, e.g. acid mediated tert-butylcarbamatedeprotection. This is typically carried out with or without solventssuch as dichloromethane, dioxane and tetrahydrofuran and mixturesthereof at temperature between 0° C. and 60° C. Typically used acids arehydrogen chloride, aqueous hydrochloric acid and trifluoroacetic acid.

In step 5, scheme 7, the free amino group of5-aminomethyl-indazole-3-carboxylic acid esters 22 is reacted with asulfonyl chloride according to methods well known to someone skilled inthe art to yield the corresponding sulfonamides 23. The reaction istypically carried out in solvents such as dichloromethane,tetrahydrofuran, acetonitrile, toluene, pyridine, triethylamine, ormixtures thereof, at temperatures between 0° C. and 110° C.

In step 6, scheme 7, the ester group of compounds 23 is removed to yieldthe corresponding acids 24, in analogy to what described in scheme 3,step 3.

In step 7, scheme 7, the compounds of general formula VI are obtainedfrom the acids 24 in analogy to what described in scheme 2, step 1.

The conversion of a compound of formula (I) into a pharmaceuticallyacceptable salt can be carried out by treatment of such a compound withan inorganic acid, for example a hydrohalic acid, such as, for example,hydrochloric acid or hydrobromic acid, or other inorganic acids such assulfuric acid, nitric acid, phosphoric acid etc. The salts can beobtained by standard methods known to the person skilled in the art,e.g. by dissolving the compound of formula (I) in a suitable solventsuch as e.g. dioxane or tetrahydrofuran and adding an appropriate amountof the corresponding acid. The products can conveniently be isolated byfiltration or by chromatography. Compounds of formula (I) which comprisean acid group such as COOH or an acid isostere can form salts withphysiologically compatible bases. Examples of such salts are alkaline,earth-alkaline and ammonium salts such as e.g. sodium, potassium,calcium and trimethylammonium salt. One method to form such a salt ise.g. by addition of 1/n equivalents of a basic salt such as e.g.M(OH)_(n), wherein M=metal or ammonium cation and n=number of hydroxideanions, to a solution of the compound in a suitable solvent (e.g.ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and toremove the solvent by evaporation or lyophilization.

The conversion of compounds of formula (I) into pharmaceuticallyacceptable esters can be carried out e.g. by treatment of a suitablecarboxy group present in the molecule with a suitable alcohol using e.g.a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), N,N-dicylohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) orO-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluoroborate(TPTU), or by direct reaction with a suitable alcohol under acidicconditions, as for example in the presence of a strong mineral acid likehydrochloric acid, sulfuric acid and the like.

Insofar as their preparation is not described in the examples, thecompounds of formula (I) as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth above. Starting materials are commercially available, known in theart or can be prepared by methods known in the art or in analogythereto.

As described above, the novel compounds of the present invention havebeen found to inhibit liver carnitine palmitoyl transferase 1 (L-CPT1)activity. The compounds of the present invention can therefore be usedin the treatment and/or prophylaxis of diseases which are modulated byL-CPT1 inhibitors, particularly diseases which are related tohyperglycemia and/or glucose tolerance disorders. Such diseases includee.g. diabetes and associated pathologies, non insulin dependent diabetesmellitus, obesity, hypertension, insulin resistance syndrome, metabolicsyndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

The invention likewise embraces compounds as described above for use astherapeutically active substances, especially as therapeutically activesubstances for the treatment and/or prophylaxis of diseases which aremodulated by L-CPT1 inhibitors, particularly as therapeutically activesubstances for the treatment and/or prophylaxis of hyperglycemia,glucose tolerance disorders, diabetes and associated pathologies, noninsulin dependent diabetes mellitus, obesity, hypertension, insulinresistance syndrome, metabolic syndrome, hyperlipidemia,hypercholesterolemia, fatty liver disease, atherosclerosis, congestiveheart failure and renal failure.

In another preferred embodiment, the invention relates to a method forthe therapeutic and/or prophylactic treatment of diseases which aremodulated by L-CPT1 inhibitors, particularly for the therapeutic and/orprophylactic treatment of hyperglycemia, glucose tolerance disorders,diabetes and associated pathologies, non insulin dependent diabetesmellitus, obesity, hypertension, insulin resistance syndrome, metabolicsyndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure, whichmethod comprises administering a compound as defined above to a humanbeing or animal.

The invention also embraces the use of compounds as defined above forthe therapeutic and/or prophylactic treatment of diseases which aremodulated by L-CPT1 inhibitors, particularly for the therapeutic and/orprophylactic treatment of hyperglycemia, glucose tolerance disorders,diabetes and associated pathologies, non insulin dependent diabetesmellitus, obesity, hypertension, insulin resistance syndrome, metabolicsyndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure.

The invention also relates to the use of compounds as described abovefor the preparation of medicaments for the therapeutic and/orprophylactic treatment of diseases which are modulated by L-CPT1inhibitors, particularly for the therapeutic and/or prophylactictreatment of hyperglycemia, glucose tolerance disorders, diabetes andassociated pathologies, non insulin dependent diabetes mellitus,obesity, hypertension, insulin resistance syndrome, metabolic syndrome,hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure. Suchmedicaments comprise a compound as described above.

Prevention and/or treatment of hyperglycemia and non insulin dependentdiabetes mellitus is the preferred indication.

The following tests were carried out in order to determine the activityof the compounds of the present invention. Background information on theperformed assays can be found in: Jackson et al., 1999, Biochem. J. 341,483-489 and Jackson et al., 2000, J. Biol. Chem. 275, 19560-19566.

Human liver and muscle CPT1 cDNAs and rat CPT2 cDNA were subcloned inpGAPZB or pGAPZA, respectively. These plasmids were used to transform P.pastoris strain X-33 via electroporation after the preparation ofelectrocompetent cells. High copy number clones were selected wherenecessary using 0.5 or 1 mg/ml Zeocin. Cultures for activitymeasurements were induced for 16 h in YPD medium (1% yeast extract, 2%peptone, 2% glucose). Crude cell extracts were prepared by disruptingthe cells with glass beads or French Press, depending on fermentersizes. After centrifugation, the cell-free extracts were resuspended incell breaking buffer (50 mM Tris, pH 7.4, 100 mM KCl, 1 mM EDTA) in thepresence of a protease inhibitor cocktail, before aliquoting andfreezing at −20° C.

CPT activity was measured using a spectrophotometric assay using5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) also called Ellman'sreagent. The HS-CoA released on the formation of acylcarnitine fromcarnitine (500 μM) and palmitoyl-CoA (80 μM) reduced DTNB (300 μM)forming 5-mercapto-(2-nitrobenzoic acid) which absorbed at 410 nm with amolar extinction coefficient of 13600 M⁻¹cm⁻¹. The assay buffercontained 120 mM KCl, 25 mM Tris, pH 7.4, 1 mM EDTA. This assay was usedfor the identification of selective inhibitors of the liver CPT1 isoformversus the muscle CPT1 and CPT2 isoforms.

The compounds according to formula (I) preferably have an IC₅₀ valuebelow 10 μM, preferably 10 nM to 10 μM, more preferably 10 nM to 5 μM.The following table shows data for some examples.

L-CPT1 inhibition Example IC₅₀ [μmol/l] 1 0.26 28 0.6 32 0.026

The compounds of formula I and/or their pharmaceutically acceptablesalts can be used as medicaments, e.g. in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatine capsules, solutions,emulsions or suspensions, rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions or suspensions orinfusion solutions, or topically, e.g. in the form of ointments, creamsor oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 2000 mg,especially about 1 to 500 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-200 mg, of a compound of formula I.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner. The mass spectrometry terms (ES⁺)=electro spray positive mode,and [M+H]=the molecular weight of the compound plus a proton.

EXAMPLES Example 1N-[1-(4-difluoromethoxy-benzyl)-1H-indazol-3-yl]-terephthalamic acid

The title compound was prepared according to the procedure illustratedin scheme 1.

Step 1. General procedure: Hydrazine monohydrate (10 equiv) was addeddropwise to a stirred solution of 2-fluorobenzonitrile in ethanol (2.5mL/mmol) at room temperature. The reaction mixture was heated underreflux for 16 hours, cooled to room temperature and concentrated invacuo. The residue was dissolved in dichloromethane (20 mL/g), driedover magnesium sulphate and concentrated in vacuo. The material wasrecrystallized from ethyl acetate/heptane to give 3-aminoindazole.

Step 2. General procedure: Dimethylformamide dimethylacetal (2.0mL/mmol) was added to 3-aminoindazole and the resulting suspensionstirred at room temperature for 16 hours and then poured onto ice/water(5 volumes). The precipitate was collected by filtration, dissolved inethyl acetate (20 mL/g), dried over magnesium sulphate and thenconcentrated in vacuo to affordN′-(1H-indazol-3-yl)-N,N-dimethylformamidine.

Step 3. Potassium tert-butoxide (1.4 g, 12.8 mmol) was added to astirred solution of N′-(1H-indazol-3-yl)-N,N-dimethylformamidine (2.0 g,10.6 mmol) in tetrahydrofuran (50 mL). 4-difluoromethoxy-benzyl bromide(3.0 g, 12.8 mmol) was then added and the reaction mixture was heated at50° C. with stirring under an atmosphere of nitrogen for 16 hours. Thereaction mixture was cooled to room temperature, water (20 mL) was addedand the mixture was extracted with dichloromethane (3×20 mL). Theorganic layer was washed with brine (20 mL), dried over sodium sulphateand concentrated in vacuo. The crude material was purified by flashcolumn chromatography (50% ethyl acetate/heptane) to affordN′-[1-(4-difluoromethoxybenzyl)-1H-indazol-3-yl]-N,N-dimethylformamidine,1.08 g (30%). LC@215 nm; Rt 1.24: 95%, m/z (ES+): 345.3 (M+H).

Step 4. Hydrazine monohydrate (1.4 mL, 30.0 mmol) was added to a stirredsolution ofN′-[1-(4-difluoromethoxybenzyl)-1H-indazol-3-yl]-N,N-dimethylformamidine(1.1 g, 3.1 mmol) in acetonitrile (50 mL) at room temperature. Thereaction mixture was heated at 60° C. for 16 hours, cooled to roomtemperature and then concentrated in vacuo. The residue was suspended inwater (15 mL) and extracted with dichloromethane (3×15 mL). The organiclayers were combined and washed with brine (15 mL), dried over sodiumsulphate and concentrated in vacuo. The residue was purified by flashcolumn chromatography (2:1 ethyl acetate/heptane) to afford1-(4-difluoromethoxybenzyl)-1H-indazol-3-ylamine, 0.63 g (70%). LC@215nm; Rt 1.27: 60%, m/z (ES+): 290.2 (M+H).

Step 5. A solution of 4-chlorocarbonylbenzoic acid methyl ester (0.074g, 0.37 mmol) in acetonitrile (2.0 mL) was added to a suspension of1-(4-difluoromethoxybenzyl)-1H-indazol-3-ylamine (0.055 g, 0.15 mmol)and Ambersep 900 carbonate resin (0.12 g, 0.45 mmol) in acetonitrile(3.0 mL). The reaction mixture was shaken at room temperature for 16hours. Polymer supported diethylenetriamine (0.060 g, 0.45 mmol) wasadded to the reaction mixture and shaking continued for a further 16hours. The reaction was filtered and concentrated in vacuo. The residuewas purified by preparative HPLC to affordN-[1-(4-difluoromethoxybenzyl)-1H-indazol-3-yl]-terephthalamic acidmethyl ester, 0.067 g (97%). LC@215 nm; Rt 1.55: 98%, m/z (ES+): 452.3(M+H).

Step 6.Lithium hydroxide (0.019 g, 0.45 mmol) was added to a stirredsolution ofN-[1-(4-difluoromethoxybenzyl)-1H-indazol-3-yl]-terephthalamic acidmethyl ester (0.067 g, 0.15 mmol) in 1:1 tetrahydrofuran/water (2.0 mL).The reaction mixture was stirred at room temperature for 6 hours thenacidified with 1N HCl (1.0 mL). A precipitate was collected and dried bysuction filtration to affordN-[1-(4-difluoromethoxybenzyl)-1H-indazol-3-yl]-terephthalamic acid,0.059 g (90%). LC@215 nm; Rt 1.42: 100%, m/z (ES+): 438.1 (M+H).

Example 2 N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-benzamide

The title compound was prepared as described for example 1, steps 1 to5. Step 5 was performed using benzoyl chloride. Yield 0.057 g (48%).LC@215 nm; Rt 1.55: 92%, m/z (ES+): 394.1 (M+H).

Example 3 Thiophene-2-carboxylic acid[1-(4-difluoromethoxy-benzyl)-1H-indazol-3-yl]-amide

The title compound was prepared as described for example 1, steps 1 to5. Step 5 was performed using thiophene-2-carbonyl chloride. Yield 0.050g (42%). LC@215 nm; Rt 1.54: 100%, m/z (ES+): 400.0 (M+H).

Example 4N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-3-fluoro-benzamide

The title compound was prepared as described for example 1, steps 1 to5. Step 5 was performed using 3-fluoro-benzoyl chloride. Yield 0.058 g(47%). LC@215 nm; Rt 1.60: 92%, m/z (ES+): 412.0 (M+H).

Example 5N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-3-methoxy-benzamide

The title compound was prepared as described for example 1, steps 1 to5. Step 5 was performed using 3-methoxy-benzoyl chloride. Yield 0.050 g(40%). LC@215 nm; Rt 1.57: 100%, m/z (ES+): 424.1 (M+H).

Example 6N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-isonicotinamide

The title compound was prepared as described for example 1, steps 1 to5. Step 5 was performed using isonicotinoyl chloride. Yield 0.0044 g(4%). LC@215 nm; Rt 1.29: 100%, m/z (ES+): 395.2 (M+H).

Example 7N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamicacid

The title compound was prepared as described for example 1, steps 1 to6. Step 1 was performed using 2,5-difluoro-benzonitrile and yielded5-fluoro-1H-indazol-3-ylamine, which was converted toN′-(5-fluoro-1H-indazol-3-yl)-N,N-dimethyl-formamidine in step 2. Step 3was performed with 4-difluoromethoxy-benzyl bromide, yieldingN′-[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-N,N-dimethyl-formamidine,which was deprotected to1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-ylamine in step 4.This was coupled to 4-chlorocarbonylbenzoic acid methyl ester in step 5and the resultingN-[1-(4-difluoromethoxybenzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamicacid methyl ester hydrdolyzed to the title compound in step 6. Yield0.0075 g (5%) over the two last steps. LC@215 nm; Rt 1.50: 93%, m/z(ES+): 455.9 (M+H).

Example 8N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide

The title compound was prepared as described for example 7, steps 1 to5. Step 5 was performed using benzoyl chloride. Yield 0.0077 g, (6%).LC@215 nm; Rt 1.58: 95%, m/z (ES+): 412.1 (M+H).

Example 9N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide

The title compound was prepared as described for example 7, steps 1 to5. Step 5 was performed using 3-fluoro-benzoyl chloride. Yield 0.0092 g(7%). LC@215 nm; Rt 1.59: 98%, m/z (ES+): 430.1 (M+H).

Example 10 Thiophene-2-carboxylic acid[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-amide

The title compound was prepared as described for example 7, steps 1 to5. Step 5 was performed using thiophene-2-carbonyl chloride. Yield0.0059 g (5%). LC@215 nm; Rt 1.59: 100%, m/z (ES+): 418.1 (M+H).

Example 11N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide

The title compound was prepared as described for example 7, steps 1 to5. Step 5 was performed using 3-methoxy-benzoyl chloride. Yield 0.0066 g(5%). LC@215 nm; Rt 1.61: 98%, m/z (ES+): 442.2 (M+H).

Example 12N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-isonicotinamide

The title compound was prepared as described for example 7, steps 1 to5. Step 5 was performed using isonicotinoyl chloride. Yield 0.0056 g(5%). LC@215 nm; Rt 1.32: 95%, m/z (ES+): 413.2 (M+H).

Example 13N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-nicotinamide

The title compound was prepared as described for example 7, steps 1 to5. Step 5 was performed using nicotinoyl chloride. Yield 0.0065 g (5%).LC@215 nm; Rt 1.35: 97%, m/z (ES+): 413.2 (M+H).

Example 14N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic acid

The title compound was prepared as described in example 7, steps 1 to 6.Step 3 was performed with 3-chloro-benzyl bromide, yieldingN′-[1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-N,N-dimethyl-formamidine,which was deprotected to1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-ylamine in step 4. This wascoupled to 4-chlorocarbonylbenzoic acid methyl ester in step 5 and theresultingN-[1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic acidmethyl ester hydrdolyzed to the title compound in step 6. Yield 0.0059 g(5%) over the last two steps. LC@215 nm; Rt 1.51: 88%, m/z (ES+): 423.9(M+H).

Example 15 N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide

The title compound was prepared as described in example 14, steps 1 to5. Step 5 was performed using benzoyl chloride. Yield 0.0075 g (7%).LC@215 nm; Rt 1.62: 93%, m/z (ES+): 380.1 (M+H).

Example 16N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide

The title compound was prepared as described in example 14, steps 1 to5. Step 5 was performed using 3-fluoro-benzoyl chloride. Yield 0.0074 g(6%). LC@215 nm; Rt 1.63: 96%, m/z (ES+): 398.1 (M+H).

Example 17N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide

The title compound was prepared as described in example 14, steps 1 to5. Step 5 was performed using 3-methoxy-benzoyl chloride. Yield 0.011 g(9%). LC@215 nm; Rt 1.64: 95%, m/z (ES+): 410.1 (M+H).

Example 18 Thiophene-2-carboxylic acid[1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide

The title compound was prepared as described in example 14, steps 1 to5. Step 5 was performed using thiophene-2-carbonyl chloride. Yield0.0046 g (4%). LC@215 nm; Rt 1.62: 100%, m/z (ES+): 386.1 (M+H).

Example 19 Furan-2-carboxylic acid[1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide

The title compound was prepared as described in example 14, steps 1 to5. Step 5 was performed using furan-2-carbonyl chloride. Yield 0.0048 g(4%). LC@215 nm; Rt 1.54: 98%, m/z (ES+): 370.1 (M+H).

Example 20N-[1-(4-Difluoromethoxy-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamicacid

The title compound was prepared as described for example 1, steps 1 to6. Step 1 was performed using 2,3-difluoro-benzonitrile and yielded7-fluoro-1H-indazol-3-ylamine, which was protected toN′-(7-fluoro-1H-indazol-3-yl)-N,N-dimethyl-formamidine in step 2. Step 3was performed using 4-difluoromethoxy-benzyl bromide, and yieldedN′-[1-(4-difluoromethoxy-benzyl)-7-fluoro-1H-indazol-3-yl]-N,N-dimethyl-formamidine,which was deprotected to1-(4-difluoromethoxy-benzyl)-7-fluoro-1H-indazol-3-ylamine in step 4.This was coupled to 4-chlorocarbonylbenzoic acid methyl ester in step 5and the resultingN-[1-(4-difluoromethoxy-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamicacid methyl ester was hydrdolyzed to the title compound in step 6. Yield0.004 g (3%) over the two last steps. LC@215 nm; Rt 1.50: 97%, m/z(ES+): 456.1 (M+H).

Example 21N-[1-(3-Chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamic acid

The title compound was prepared as in example 20, steps 1 to 6. Step 3was performed with 3-chloro-benzyl bromide, yieldingN′-[1-(3-chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-N,N-dimethyl-formamidine,which was deprotected to1-(3-chloro-benzyl)-7-fluoro-1H-indazol-3-ylamine in step 4. This wascoupled to 4-chlorocarbonylbenzoic acid methyl ester in step 5 and theresultingN-[1-(3-chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamic acidmethyl ester hydrdolyzed to the title compound in step 6. Yield 0.0032 g(3%) over the two last steps. LC@215 nm; Rt 1.52: 86%, m/z (ES+): 424.1(M+H).

Example 22 Thiophene-2-carboxylic acid[1-(3-chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-amide

The title compound was prepared as in example 21, step 1 to 5. Step 5was performed using thiophene-2-carbonyl chloride. Yield 0.0036 g (3%).LC@215 nm; Rt 1.71: 97%, m/z (ES+): 386.1 (M+H).

Example 23N-[1-(3-Chloro-benzyl)-6-fluoro-1H-indazol-3-yl]-terephthalamic acid

The title compound was prepared as described for example 1, steps 1 to6. Step 1 was performed using 2,4-difluoro-benzonitrile and yielded6-fluoro-1H-indazol-3-ylamine, which was protected toN′-(6-fluoro-1H-indazol-3-yl)-N,N-dimethyl-formamidine in step 2. Step 3was performed using 3-chloro-benzyl bromide, and yieldedN′-[1-(3-chloro-benzyl)-6-fluoro-1H-indazol-3-yl]-N,N-dimethyl-formamidine,which was deprotected to1-(3-chloro-benzyl)-6-fluoro-1H-indazol-3-ylamine in step 4. This wascoupled to 4-chlorocarbonylbenzoic acid methyl ester in step 5 and theresultingN-[1-(3-chloro-benzyl)-6-fluoro-1H-indazol-3-yl]-terephthalamic acidmethyl ester was hydrdolyzed to the title compound in step 6. Yield0.0016 g (1%) over the two last steps. LC@215 nm; Rt 1.50: 86%, m/z(ES+): 424.1 (M+H).

Example 24 Thiophene-2-carboxylic acid[1-(4-difluoromethoxy-benzyl)-6-fluoro-1H-indazol-3-yl]-amide

The title compound was prepared as in example 23, steps 1 to 5. Step 3was performed with 4-difluoromethoxy-benzyl bromide, yieldingN′-[1-(4-difluoromethoxy-benzyl)-6-fluoro-1H-indazol-3-yl]-N,N-dimethyl-formamidine,which was deprotected to1-(4-difluoromethoxy-benzyl)-6-fluoro-1H-indazol-3-ylamine in step 4.This was coupled to thiophene-2-carbonyl chloride in step 5. Yield0.0038 g (3%). LC@215 nm; Rt 1.59: 98%, m/z (ES+): 418.1 (M+H).

Example 25 Thiophene-2-carboxylic acid (1-benzyl-1H-indazol-3-yl)-amide

The title compound was prepared as described for example 1, steps 1 to5. Step 3 was performed using benzyl bromide, yieldingN′-(1-benzyl-1H-indazol-3-yl)-N,N-dimethyl-formamidine, which wasdeprotected to 1-benzyl-1H-indazol-3-ylamine in step 4. This was coupledto thiophene-2-carbonyl chloride in step 5. Yield 0.056 g (56%). LC@215nm; Rt 1.47: 100%, m/z (ES+): 334.1 (M+H).

Example 26 1-ethyl-5-(3-propyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide

The title compound was prepared according to the procedure illustratedin schemes 3 and 6.

Step 1. Iodoethane (11.6 mL, 145 mmol) was added to a suspension of5-nitro-1H-indazole-3-carboxylic acid (10.0 g, 48 mmol) and K₂CO₃ (20.3g, 145 mmol) in dimethylformamide (100 mL). The reaction mixture wasshaken at room temperature for 18 hours. Again, iodoethane (11.6 mL, 145mmol) and K₂CO₃ (20.3 g, 145 mmol) were added to the reaction mixtureand shaken for another 18 hours, then heated at 80° C. for a further 18hours. The reaction mixture was saturated with water (300 mL) andextracted with dichloromethane (3×300 mL). The organic phases werecombined and washed with brine (300 mL), dried over magnesium sulphateand concentrated in vacuo. The residue was purified by flash columnchromatography (10% to 50% ethyl acetate/heptane) to afford1-ethyl-5-nitro-1H-indazole-3-carboxylic acid ethyl ester, 4.45 g (35%).LC@215 nm; Rt 1.41: 94%, m/z (ES+): 264.2 (M+H).

Step 2. Lithium hydroxide (2.5 g, 59.6 mmol) was added to a solution of1-ethyl-5-nitro-1H-indazole-3-carboxylic acid ethyl ester (3.8 g, 14.4mmol) in a 1:1 mixture of tetrahydrofuran/water (60 mL). The reactionmixture was shaken for 18 hours. The reaction mixture was acidified topH 1 with concentrated HCl and extracted with ethyl acetate (3×50 mL).The combined organic layers were dried over magnesium sulphate andconcentrated in vacuo. The resultant solid was suspended in toluene andthe solvent was evaporated to afford1-ethyl-5-nitro-1H-indazole-3-carboxylic acid, 3.85 g (97%). LC@215 nm;Rt 1.08: 100%, m/z (ES+): 236.2 (M+H).

Step 3. Pentafluorophenyltrifluoroacetate (1.85 mL, 10.8 mmol) was addeddropwise to a solution of 1-ethyl-5-nitro-1H-indazole-3-carboxylic acid(1.59 g, 6.77 mmol) in 1:1 mixture of tetrahydrofuran/pyridine (16 mL)at 0° C. The reaction mixture was allowed to warm up to room temperatureand was shaken for 16 hours. The solution was concentrated in vacuo andthe residue was taken up in ethyl acetate (50 mL). The solution waswashed with 0.1N HCl (3×40 mL) followed by a saturated sodiumbicarbonate solution (40 mL). The organic layer was dried over magnesiumsulphate and concentrated in vacuo. The residue was dissolved indimethylformamide (16 mL) and triethylamine (1.3 mL, 9.36 mmol) to whichthiophene-2-methylamine (1.16 g, 10.2 mmol) was added. The reactionmixture was shaken at room temperature for 16 hours then diluted withdichloromethane (50 mL) and washed 1N HCl (3×40 mL) and brine (3×40 mL).The organic layer was dried over magnesium sulphate and concentrated invacuo. The residue was recrystallized from dichloromethane to afford1-ethyl-5-nitro-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide, 1.67 g (75%). LC@215 nm; Rt 1.45: 96%, m/z(ES+): 331.3 (M+H).

Step 4. 1N HCl (2.0 mL) was added to a suspension of iron powder (3.0 g)and 1-ethyl-5-nitro-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide (1.67 g, 5.37 mmol) in a 1:1 mixture ofethanol/water (15 mL). The reaction mixture was heated at 80° C. for 8hours, then cooled to room temperature, filtered through Celite® andconcentrated in vacuo. The residue was dissolved in ethyl acetate (20mL) and washed with 1N HCl (3×10 mL), followed by saturated sodiumbicarbonate (10 mL). The organic layer was dried over magnesium sulphateand concentrated in vacuo. The residue was purified by flash columnchromatography (20% to 50% ethyl acetate/heptane) to afford5-amino-1-ethyl-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide, 0.44 g (29%). LC@215 nm; Rt 1.03: 88%, m/z(ES+): 301.3 (M+H).

Step 5. Propyl isocyanate (0.011 g, 0.13 mmol) was added to a solutionof 5-amino-1-ethyl-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide (0.027 g, 0.089 mmol in dichloroethane (2.0mL). The reaction mixture was shaken at room temperature for 16 hoursthen concentrated in vacuo. The residue was purified by preparative HPLCto afford 1-ethyl-5-(3-propyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide, 0.0099 g (29%). LC@215 nm; Rt 1.38: 92%,m/z (ES+): 386.4 (M+H).

Example 27 1-Ethyl-5-(3-isopropyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide

The title compound was prepared as described in example 26, steps 1 to5. Step 5 was performed using isopropyl isocyanate. Yield 0.014 g (42%).LC@215 nm; Rt 1.37: 97%, m/z (ES+): 386.4 (M+H).

Example 28 1-Ethyl-5-(3-phenethyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide

The title compound was prepared as described in example 26, steps 1 to5. Step 5 was performed using phenethyl isocyanate. Yield 0.011 g (27%).LC@215 nm; Rt 1.51: 97%, m/z (ES+): 448.4 (M+H).

Example 29N-[1-Ethyl-5-(3-ethyl-ureido)-1H-indazol-3-yl]-2-thiophen-2-yl-acetamide

The title compound was prepared as described in example 26, steps 1 to5. Step 5 was performed using ethyl isocyanate. Yield 0.017 g (51%).LC@215 nm; Rt 1.30: 97%, m/z (ES+): 372.3 (M+H).

Example 30 1-(4-Nitro-benzyl)-1H-indazole-3-carboxylic acid(pyridin-3-ylmethyl)-amide

The title compound was prepared according to the procedure illustratedin scheme 3. Step 1. A solution of indazole-3-carboxylic acid (10.0 g,61.7 mmol) in tetrahydrofuran (150 mL) was treated withcarbonyldiimidazole (10.5 g, 64.7 mmol). The mixture was warmed toreflux and stirred for 4 hours. 2-Trimethylsilanyl-ethanol (9.70 mL,67.8 mmol) was added and the mixture was warmed at reflux for further 10hours. A further aliquot of 2-trimethylsilanyl-ethanol (7.0 mL, 49 mmol)was added and the mixture stirred at reflux for 24 hours. The mixturewas quenched with water (20 mL) and part of the solvent was evaporated.The residual slurry was partitioned between water and diethyl ether. Theorganic phase was washed three times with water, then with saturatedNH₄Cl and water. The organic phase was then dried with sodium sulphateand evaporated. The residue was suspended in hexane and sonicated, andthe precipitate was filtered off, yielding crude1H-indazole-3-carboxylic acid 2-trimethylsilanyl-ethyl ester, 12.6 g(77.8%), which was used crude.

Step 2. A solution of 1H-indazole-3-carboxylic acid2-trimethylsilanyl-ethyl ester (3.50 g, 13.3 mmol) in dimethylformamide(50 mL) was treated with 4-nitro-benzyl chloride (2.40 g, 14.0 mmol).The resulting solution was cooled to 0° C. and sodium hydride (55% inmineral oil, 0.750 g, 17.3 mmol) was added in four portions. Afterstirring for 10 min at 0° C., the mixture was left to warm to roomtemperature and stirred for 20 hours. The mixture was partitionedbetween diethyl ether and a 10% KHSO₄ solution. The organic phase wasseparated and washed with water and brine, dried over magnesium sulphateand evaporated. The residue was purified by flash chromatography(heptane/dichloromethane gradient), yielding1-(4-nitro-benzyl)-1H-indazole-3-carboxylic acid2-trimethylsilanyl-ethyl ester as a yellow amorphous solid, 1.53 g(29%), m/z (ISP): 370.1 (M+H).

Step 3. A solution of 1-(4-nitro-benzyl)-1H-indazole-3-carboxylic acid2-trimethylsilanyl-ethyl ester (1.24 g, 3.12 mmol) in tetrahydrofuran(35 mL) was cooled to 0° C. and treated with a solution oftetrabutylammonium fluoride monohydrate (1.20 g, 3.75 mmol) intetrahydrofuran (15 mL). The mixture was stirred at room temperature for1 hour. After cooling back to 0° C., again a solution oftetrabutylammonium fluoride monohydrate (0.79 g, 2.5 mmol) intetrahydrofuran (10 mL) was added dropwise. The mixture was stirred forone further hour at room temperature, then partitioned between diethylether and a 10% KHSO₄ solution. The organic phase was separated andwashed with water and brine, dried over magnesium sulphate andevaporated. Crude 1-(4-nitro-benzyl)-1H-indazole-3-carboxylic acid wasobtained as a yellow solid, 0.99 g (100%), m/z (ISP): 296.5 (M−H).

Step 4. A solution of 1-(4-nitro-benzyl)-1H-indazole-3-carboxylic acid(0.15 g, 0.50 mmol) in dichloromethane (4.0 mL) was treated at roomtemperature with pyridin-3-yl-methylamine (0.055 g, 0.50 mmol),1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.12 g,0.61 mmol) and 4-dimethylamino-pyridine (0.092 g, 0.76 mmol). Themixture was stirred at room temperature for 2 hours. The solvent wasevaporated and the residue purified by flash chromatography(heptane/ethyl acetate gradient) to yield1-(4-nitro-benzyl)-1H-indazole-3-carboxylic acid(pyridin-3-ylmethyl)-amide as a light yellow solid, 0.033 g (17%), m/z(ISP): 388.0 (M+H).

Example 31 1-(4-Difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide

The title compound was prepared according to the procedure illustratedin scheme 2.

Step 1. A solution of indazole-3-carboxylic acid (1.50 g, 9.25 mmol) indimethylformamide (70 mL) was treated with thiophene-2-ylmethyl-amine(1.57 g, 13.9 mmol), diisopropylethyl amine (3.59 g, 4.70 mL, 27.8 mmol)and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (4.46 g, 13.9 mmol.). The mixture was stirred atroom temperature for 16 hours, then diluted with water. The resultingslurry was extracted three times with ethyl acetate. The combinedorganic phases were dried with sodium sulphate and evaporated. Theresidue was suspended in dichloromethane and sonicated. The precipitatedwas filtered and dried under vacuum to afford 1H-indazole-3-carboxylicacid (thiophen-2-ylmethyl)-amide, 1.46 g (61%), m/z (ISP): 256.0 (M−H).

Step 2. A solution of 1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide (0.030 g, 0.12 mmol) in tetrahydrofuran(0.44 mL) was treated with a solution of potassium tert-butylate (0.13mmol) in tetrahydrofuran (0.40 mL). The mixture was stirred at 60° C.for 30 min, then treated with a solution of 4-difluoromethoxy-benzylbromide (0.034 g, 0.14 mmoL) in tetrahydrofuran (0.40 mL). The mixturewas stirred at 60° C. for 3 h, then the volatiles were evaporated. Theresidue was redissolved in acetonitrile and purified by preparative HPLC(Column: Zorbax Eclipse XBD-C18, 21.2×50 mm, 5 um, PN 970050-902, SNUSDN001065. Gradient: 0-0.5 min: 10% acetonitrile in (water+0.1% HCO₂H),0.5-2.4 min: increasing of acetonitrile from 10% to 95%, 2.4-4.75 min:95% of acetonitrile, 4.75-4.8 min: decreasing acetonitrile from 95% to10%. Program end at 5 min. Flow: 30 mL/min) to yield1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide, 0.036 g (73%), m/z (ISP): 414.1 (M+H).

Example 32 1-(3-Trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide

The title compound was obtained as described for example 32, using3-trifluoromethyl-benzyl bromide in step 2. Yield 0.036 g (73%), m/z(ES+): 416.0 (M+H).

Example 334-({[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-methyl)-benzoicacid

The title compound was prepared as illustrated in scheme 3 and 5.

Step 1. A solution of 5-fluoro-isatin (10.0 g, 60.6 mmol) in 1N NaOH (61mL) was stirred at 60° C. for 20 min. The solution was cooled to 3° C.and a solution of sodium nitrite (4.59 g, 66.6 mmol) in water (20 mL)was added, and the mixture stirred for 20 min. The resulting solutionwas added dropwise to a cooled solution of concentrated sulfuric acid(3.64 ml, 67.9 mmol) in water (130 mL) so that the temperature remainedbetween 0 and 4° C. The mixture was stirred at 0-5° C. for 2 h, thenadded portionwise to a solution of SnCl₂ (22.0 g, 116 mmol) inconcentrated HCl (46 mL). The mixture was left for 5 hours, upon whichcrystallization took place. The crystals were filtered off, washing withwater, to yield 5-fluoro-1H-indazole-3-carboxylic acid as a white solid(9.76 g). The raw material was then dissolved in tetrahydrofuran (100mL) and treated with carbonyldiimidazole (CDI, 9.82 g, 60.6 mmol). Themixture was warmed to reflux and stirred for 2 hours. EtOH (100 mL) wasthen added, and the mixture stirred at reflux for further 5 hours. Thevolatiles were evaporated and the residue redissolved in warm ethylacetate. The organic solution was washed with 1N HCl, and then withwater, dried with sodium sulphate and evaporated. The raw material waspurified by flash chromatography (heptane/ethyl acetate 1:1, followed bya second chromatography with dichloromethane/diethyl ether 9:1) to yield5-fluoro-1H-indazole-3-carboxylic acid ethyl ester as an off-whitesolid, 6.22 g (49.3%).

Step 2. A solution of 5-fluoro-1H-indazole-3-carboxylic acid ethyl ester(2.50 g, 12.0 mmol) in dimethylformamide (30 mL) was treated with4-difluoromethoxy-benzyl chloride (2.59 g, 13.2 mmol). The resultingsolution was cooled to 0° C. and sodium hydride (55% in mineral oil,0.680 g, 15.6 mmol) was added in three portions. After stirring for 10min at 0° C., the mixture was left to warm to room temperature andstirred for 2 hours. The mixture was partitioned between diethyl etherand a 10% KHSO₄ solution. The organic phase was separated and washedwith water and brine, dried over magnesium sulphate and evaporated. Theresidue was purified by flash chromatography (heptane/ethyl acetategradient), yielding1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acidethyl ester as a yellow crystalline solid, 1.76 g (40%), m/z (ISP):365.0 (M+H).

Step 3. A solution of1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acidethyl ester (1.68 g, 4.61 mmol) in tetrahydrofuran (20.0 mL) was treatedwith a 1N solution of lithium hydroxide at 0° C. The mixture was stirredat 0° C. for 15 min, then at room temperature for 3 hours and at 50° C.for 4 hours. After cooling to room temperature, the mixture wasacidified with HCl 1N (14 mL) and extracted with ethyl acetate. Thecombined organic phases were dried over magnesium sulphate andevaporated. The residue was suspended in heptane and the precipitate wasfiltered and dried under vacuum. 5-Fluoro-1H-indazole-3-carboxylic acidwas obtained as a yellow solid, 1.5 g (97%), m/z (ISP): 335.2 (M−H).

Step 4. A solution of 5-fluoro-1H-indazole-3-carboxylic acid (0.25 g,0.74 mmol) in dichloromethane (5.0 mL) was treated with triethylamine(0.083 g, 0.11 mL, 0.82 mmol), 4-dimethylamino pyridine (0.14 g, 1.1mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride(0.17 g, 0.89 mmol). 4-Aminomethyl-benzoic acid methyl ester (0.16 g,0.82 mmol) was added. The mixture was stirred at room temperature for 16hours, then partitioned between diethyl ether and 1N HCl. The organicphase was washed with water and brine, dried over magnesium sulphate andevaporated. The residue was purified by flash chromatography(heptane/ethyl acetate gradient), to yield4-({[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-methyl)-benzoicacid methyl ester as a yellow solid, 0.19 g (54%), m/z (ISP): 484.5(M+H).

Step 5.4-({[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-methyl)-benzoicacid methyl ester (0.16 g, 0.32 mmol) was dissolved in tetrahydrofuran(2.0 mL) and treated at 0° C. with 1N LiOH. The mixture was stirred atroom temperature for 3 hours, then at 50° C. for 5 hours. After coolingback to room temperature, the reaction mixture was acidified with 1N HC1(1.0 mL) and extracted with ethyl acetate. The organic phase was driedover magnesium sulphate and evaporated. The residue was suspended in aheptane/diethyl ether mixture and the precipitate filtered to yield4-({[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-methyl)-benzoicacid as an off-white solid, 0.13 g (89%), m/z (ISP): 468.0 (M−H).

Example 34(2-{[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound was prepared as illustrated for example 33, steps 1to 5. Step 4 was performed using 2-amino-thiazol-4-yl)-acetic acid ethylester, yielding(2-{[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrdolyzed to the title compound in step 5.Yield 0.045 g (72%), m/z (ISP): 475.1 (M−H).

Example 351-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid[4-(1H-tetrazol-5-yl)-phenyl]-amide;

The title compound was prepared as illustrated for example 33, steps 1to 4. Step 4 was performed using 4-(1H-tetrazol-5-yl)-phenylaminehydrochloride. Yield 0.027 g (13%), m/z (ISP): 480.0 (M+H).

4-(1H-Tetrazol-5-yl)-phenylamine hydrochloride was prepared as describedbelow: A solution of 4-aminobenzonitrile (5.00 g, 42.3 mmol) indichloromethane (50 mL) was treated with di-tert-butyl dicarbonate (9.52g, 42.3 mmol) and dimethylaminopyridine (0.300 g, 2.46 mmol) and heatedat reflux for 20 h. Further di-tert-butyl dicarbonate (2.00 g, 9.16mmol) was added, and the mixture refluxed for further 10 h. Anotheraliquot of di-tert-butyl dicarbonate (1.00 g, 4.08 mmol) was added andthe mixture refluxed for further 18 h. The mixture was partitionedbetween ethyl acetate and 1N NH₄Cl. The organic phase was separated andwashed with water, then dried with magnesium sulphate and evaporated,yielding crude (4-cyano-phenyl)-carbamic acid tert-butyl ester (11.0 g).The raw material was dissolved in dimethylformamide (100 mL) and treatedwith NaN₃ (8.25 g, 127 mmol) and NH₄Cl (6.79 g, 127 mmol). The mixturewas warmed at 140° C. and stirred for 4 h. The mixture was thenpartitioned between diethyl diethyl ether and 1N HCl. The organic phasewas separated and washed with water, then dried with magnesium sulphateand evaporated. The residue was taken up in diethyl diethyl ether andfiltered, to afford crude [4-(1H-tetrazol-5-yl)-phenyl]-carbamic acidtert-butyl ester as an off-white solid (7.30 g).

The raw material (4.55 g) was then dissolved in dioxane (25 mL) andtreated with a 4N solution of HCl in dioxane (75 mL). The mixture wasstirred at room temperature for 20 h, then the volatiles evaporated andthe residue dried under high vacuum. The title compound was obtained asan off-white crystalline solid, 4.0 g (76%).

Example 361-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide

The title compound was prepared as illustrated for example 33, steps 1to 4. Step 4 was performed using 4-(1H-tetrazol-5-yl)-benzylaminehydrochloride. Yield 0.041 g (19%), m/z (ISP): 494.4 (M+H).

4-(1H-Tetrazol-5-yl)-benzylamine hydrochloride was prepared in analogyto what described in example 35 for the synthesis of4-(1H-tetrazol-5-yl)-phenylamine hydrochloride, using4-aminomethyl-benzonitrile (10 g, 75.7 mmol) as starting material.4-(1H-Tetrazol-5-yl)-benzylamine hydrochloride was obtained as anoff-white crystalline solid, 17.5 g (94%).

Example 37(4-{[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-2-methyl-phenoxy)-aceticacid

The title compound was prepared as illustrated for example 33, steps 1to 5. Step 4 was performed using (4-amino-2-methyl-phenoxy)-acetic acidmethyl ester, yielding(4-{[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-2-methyl-phenoxy)-aceticacid methyl ester which was hydrdolyzed to the title compound in step 5.Yield 0.095 g (50%), m/z (ISP): 500.3 (M+H).

Example 381-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide

The title compound was prepared as illustrated for example 33, steps 1to 4. Step 4 was performed using3-(4-amino-phenyl)-4H-[1,2,4]oxadiazol-5-one. Yield 0.11 g (57%), m/z(ISP): 494.0 (M−H).

3-(4-Amino-phenyl)-4H-[1,2,4]oxadiazol-5-one was prepared as follows:

Crude (4-cyano-phenyl)-carbamic acid tert-butyl ester (see example 35)(3.00 g, 13.7 mmol) was dissolved in methanol (30 mL) and treated withhydroxylamine hydrochloride (1.91 g, 27.5 mmol) and sodiumhydrogenocarbonate (2.31 g, 27.5 mmol). The mixture was warmed to refluxfor 4 hours, then the volatiles were evaporated. The residue was takenup in diethyl ether and the solution was washed with water, saturatedsodium hydrogenocarbonate and brine, dried over magnesium sulphate andevaporated.

Part of the crude residue (0.502 g) was dissolved in tetrahydrofuran (10mL) and treated with carbonyl diimidazole (0.42 g, 2.6 mmol). Themixture was heated at reflux for 2 hours, then partitioned between ethylacetate and 1N HCl. The organic phase was dried over magnesium sulphateand evaporated. The crude (0.45 g) was dissolved in a 4N solution of HClin dioxane (10 mL) and stirred at room temperature for 20 hours. Thevolatiles were evaporated to yield3-(4-amino-phenyl)-4H-[1,2,4]oxadiazol-5-one as an off-white solid, 0.35g (99% crude yield), which was used crude.

Example 394-{[5-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in example 33, steps 1 to5. Step 2 was performed using 3-trifluoromethyl-benzyl chloride, andyielded 1-(3-trifluoromethyl-benzyl)-5-fluoro-1H-indazole-3-carboxylicacid ethyl ester, which was hydrdolyzed to1-(3-trifluoromethyl-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid instep 3. This was coupled to 4-amino-benzoic acid ethyl ester in step 4,and the resulting4-{[5-fluoro-1-(3-trifluoromethyl-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-benzoicacid ethyl ester was hydrdolyzed to the title compound in step 5. Yieldover the last two steps 0.087 g, (41%), m/z (ISP): 458.5 (M+H).

Example 405-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid[4-(1H-tetrazol-5-yl)-phenyl]-amide

The title compound was prepared as example 39, steps 1 to 4. Step 4 wasperformed using 4-(1H-tetrazol-5-yl)-phenylamine hydrochloride (seeexample 35). Yield 0.015 g (7%), m/z (ISP): 480.1 (M−H).

Example 415-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide

The title compound was prepared as example 39, steps 1 to 4. Step 4 wasperformed using 4-(1H-tetrazol-5-yl)-benzylamine hydrochloride (seeexample 36). Yield 0.034 g (16%), m/z (ISP): 494.4 (M−H).

Example 42 1-(4-Carbamoyl-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide

The title compound was prepared as follows:

Step 1. 1H-indazole-3-carboxylic acid ethyl ester (2.00 g, 10.5 mmol)was dissolved in acetonitrile (20.0 mL) and treated with cesiumcarbonate (4.45 g, 11.0 mmol) and 4-bromomethyl benzonitrile (2.20 g,11.0 mmol). The mixture was stirred at room temperature for 2 hours,then diluted with dimethylformamide (10 mL) and stirred for further 16hours. The mixture was partitioned between diethyl ether and water andthe organic phase was washed with 1N HCl (30 mL), water and brine, driedover magnesium sulphate and evaporated. The residue was purified byflash chromatography (heptane/ethyl acetate gradient) to yield1-(4-cyano-benzyl)-1H-indazole-3-carboxylic acid ethyl ester as a lightyellow solid, 1.94 g (60%), m/z (ISP): 306.3 (M+H).

Step 2. 1-(4-cyano-benzyl)-1H-indazole-3-carboxylic acid ethyl ester(0.80 g, 2.6 mmol) was taken up in concentrated sulfuric acid and warmedto 50° C. After 30 min at 50° C., the mixture was poured over ice andthe resulting slurry extracted with ethyl acetate. The organic phase waswashed with water and brine until neutral pH, dried over magnesiumsulphate and evaporated. The residue was suspended in heptane and theprecipitate filtered to yield1-(4-carbamoyl-benzyl)-1H-indazole-3-carboxylic acid ethyl ester as acolorless solid, 0.79 g (93%), m/z (ISP): 324.4 (M+H).

1-(4-Carbamoyl-benzyl)-1H-indazole-3-carboxylic acid ethyl ester wasfurther processed in analogy to example 33, steps 3 and 4. The compoundwas hydrdolyzed to 1-(4-carbamoyl-benzyl)-1H-indazole-3-carboxylic acidin step 3 and coupled to 4-(1H-tetrazol-5-yl)-benzylamine hydrochloride(see example 36) in step 4 to yield the title compound. Yield 0.114 g(26%) over the last two steps, m/z (ISP): 453.3 (M+H).

Example 43 1-(4-Carbamoyl-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide

The title compound was prepared as follows:

1-(4-Cyano-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide (0.17 g, 0.37 mmol) was taken up inconcentrated sulfuric acid and stirred at room temperature for 6 hours.The mixture was poured over ice and the resulting suspension wasfiltered, washing the precipitate with water. The filtrated was driedunder vacuum to yield the title compound as a light yellow solid, 0.063g (36%), m/z (ISP): 471.4 (M+H).

1-(4-Cyano-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide was prepared in analogy to example 33,steps 1 to 4. Step 2 was performed with 4-bromomethyl benzonitrile,yielding 1-(4-cyano-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid ethylester, which was hydrdolyzed to1-(4-cyano-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid in step 3.This was coupled to 4-(1H-tetrazol-5-yl)-benzylamine hydrochloride (seeexample 36) in step 4, to yield1-(4-cyano-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide as a light yellow solid. Yield 0.203 g(53%), m/z (ISP): 453.1 (M+H).

Example 441-(5-Chloro-2-methoxy-benzyl)-5-fluoro-3-[4-(1H-tetrazol-5-yl)-phenylsulfanylmethyl]-1H-indazole

The title compound was prepared according to what illustrated in schemes3 and 4.

Step 1. A solution of 5-fluoro-1H-indazole-3-carboxylic acid ethyl ester(see example 33) (1.70 g, 8.30 mmol) in dimethylformamide (25 mL) wastreated with 4-chloro-2-chloromethyl-1-methoxy-benzene (1.75 g, 9.10mmol) and cooled to 0° C. Sodium hydride (55% suspension in mineral oil,0.470 g, 10.8 mmol) was added in portions over 10 min. After stirringfor 15 min at 0° C., the mixture was left to warm to room temperatureand stirred for 16 hours. The reaction mixture was partitioned betweendiethyl ether and 1N HCl (30 mL). The organic phase was washed withwater and brine until neutral, dried with magnesium sulphate andevaporated. The residue was purified by flash chromatography(heptane/ethyl acetate gradient) to yield1-(5-chloro-2-methoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acidethyl ester as a yellow solid, 2.1 g (70%), m/z (ISP): 363.3 (M+H).

Step 2. 1-(5-Chloro-2-methoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylicacid ethyl ester (1.2 g, 3.3 mmol) was dissolved in tetrahydrofuran (15mL) and the solution cooled to −75° C. A 1.2 M solution ofdiisobutylaluminium hydride in toluene (9.10 mL, 10.9 mmol) was addedwithin 15 min, so that the temperature did not exceed −67° C. Themixture was then stirred at room temperature for 1 hour. After coolingto 0° C., the reaction was quenched with 2N HCl (11 mL), and stirredvigorously for 15 min. The resulting slurry was extracted with diethylether. The combined organic phases were washed with water and brineuntil neutral pH, dried over magnesium sulphate and evaporated. Theresidue was purified by flash chromatography (heptane/ethyl acetategradient) to yield[1-(5-chloro-2-methoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-methanol as ayellow, crystalline solid, 0.83 g (78%), m/z (ISP): 321.0 (M+H).

Step 3. A solution of[1-(5-chloro-2-methoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-methanol (0.78g, 2.4 mmol) in dichloromethane (8.0 mL) was treated at 0° C. withthionyl chloride (0.23 mL, 3.2 mmol). After stirring at 0° C. for 10min, the mixture was warmed to room temperature and stirred for 1 hour.The mixture was partitioned between water and dichloromethane, theorganic phase was dried with magnesium sulphate and evaporated. Theresidual crystalline solid was crude1-(5-chloro-2-methoxy-benzyl)-3-chloromethyl-5-fluoro-1H-indazole, whichwas used as such. Yield 0.81 g (98%), m/z (ISP): 339.1 (M+H).

Step 4.1-(5-Chloro-2-methoxy-benzyl)-3-chloromethyl-5-fluoro-1H-indazole (0.2g, 0.6 mmol) was dissolved in acetonitrile (3.0 mL) and treated with4-mercapto-benzonitrile (0.080 g, 0.60 mmol) and cesium carbonate (0.27g, 0.80 mmol). After 10 min, the suspension was diluted withdimethylformamide (1.0 mL). The mixture was stirred at room temperaturefor 16 hours, then partitioned between diethyl ether and water. Theorganic phase was washed with water and brine, dried over magnesiumsulphate and evaporated. The residue was suspended in diethyl ether andthe precipitate filtered and dried under high vacuum to yield4-[1-(5-chloro-2-methoxy-benzyl)-5-fluoro-1H-indazol-3-ylmethylsulfanyl]-benzonitrileas a white solid, 0.16 g (63%), m/z (ISP): 438.1 (M+H).

Step 5.4-[1-(5-Chloro-2-methoxy-benzyl)-5-fluoro-1H-indazol-3-ylmethylsulfanyl]-benzonitrile(0.14 g, 0.30 mmol) was dissolved in dimethylformamide (1.0 mL) andtreated with ammonium chloride (0.050 g, 0.95 mmol) and sodium azide(0.060 g, 0.95 mmol). The mixture was warmed to 140° C. and stirred for24 hours. After cooling to room temperature, the reaction mixture wastreated with 1N HCl and stirred for 20 min. The slurry was diluted withacetone and extracted with diethyl ether. The organic phase was washedwith water and brine, dried over magnesium sulphate and evaporated. Theresidue was purified by flash chromatography (dichloromethane/methanolgradient) to yield1-(5-chloro-2-methoxy-benzyl)-5-fluoro-3-[4-(1H-tetrazol-5-yl)-phenylsulfanylmethyl]-1H-indazoleas alight yellow solid, 0.009 g (6%), m/z (ISP): 481.2 (M+H).

4-Chloro-2-chloromethyl-1-methoxy-benzene, used in step 1, was preparedas follows: A cooled (0° C.) solution of(5-chloro-2-methoxy-phenyl)-methanol (4.54 g, 26.3 mmol) indichloromethane (50 mL) was treated with thionyl chloride (2.01 mL, 27.7mmol), which was added dropwise over 10 min. The mixture was stirred atroom temperature for 16 h, then partitioned between diethyl ether andwater. The organic phase was dried with sodium sulphate and evaporated.The residue was pure 4-chloro-2-chloromethyl-1-methoxy-benzene, 4.93 g(98%), and was used as such.

Example 45 1-(4-Difluoromethoxy-benzyl)-1H-indazole-3,6-dicarboxylicacid 6-amide 3-[4-(1H-tetrazol-5-yl)-benzylamide]

The title compound was prepared as follows:

6-Cyano-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide (0.077 g, 0.15 mmol) was dissolved intetrahydrofuran (0.6 mL) and ethanol (0.6 mL) and treated with a 1Nsolution of LiOH (0.6 mL, 0.6 mmol). The mixture was stirred at 50° C.for 9 hours, then quenched with 1N HCl (0.65 mL). The resultingsuspension was filtered washing with water and the residue dried undervacuum to yield the title compound as a light yellow solid, 0.034 g(43%), m/z (ISP): 519.3 (M+H).

6-Cyano-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide was prepared in analogy to example 33,steps 2 to 4. Step 2 was performed using6-cyano-1H-indazole-3-carboxylic acid ethyl ester (prepared from 6-cyanoindole according to the method described in J. Med. Chem. 1997, 2843)and yielded6-cyano-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid ethylester, which was hydrdolyzed to6-cyano-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid instep 3. This was coupled to 4-(1H-tetrazol-5-yl)-benzylaminehydrochloride (see example 36) in step 4, to yield6-cyano-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide as a colorless solid. Yield 0.083 g(38%), m/z (ISP): 501.2 (M+H).

Example 461-(4-Difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide

The title compound was prepared as illustrated in scheme 7.

Step 1. A suspension of 6-cyano-1H-indazole-3-carboxylic acid ethylester (J. Med. Chem. 1997, 2843) (2.50 g, 11.6 mmol) in ethanol (50 mL)and chloroform (2.5 mL) was treated with platinum oxide. The flask wasevacuated and filled with hydrogen. The mixture was stirred at roomtemperature for 2 hours. Methanol (30 mL) was added, and the mixture wasstirred for further 28 hours. The solids were filtered, and the filtrateevaporated. The raw material was purified by trituration in diethylether to yield 6-aminomethyl-1H-indazole-3-carboxylic acid ethyl esterhydrochloride as a brown crystalline solid, 2.45 g (96%). m/z (ISP):220.3 (M+H⁺); ¹H NMR: δ_(H) (300 MHz; CDCl₃): 14.20 (1H, s); 8.54 (3H,bs); 8.08 (1H, d); 7.84 (1H, s); 7.45 (1H, d); 4.40 (2H, q); 4.20 (2H,s); 1.38 (3H, t).

Step 2. A solution of 6-aminomethyl-1H-indazole-3-carboxylic acid ethylester hydrochloride (1.2 g, 4.9 mmol) in dichloromethane (30 mL) wastreated with triethylamine (1.50 g, 14.7 mmol) and a solution ofdi-tert-butyl dicarbonate (1.15 g, 5.10 mmol) in dimethylformamide (10mL). The mixture was stirred at room temperature for 1 hour. Thereaction mixture was partitioned between diethyl ether and 1N HCl. Theorganic phase was washed with water and brine until neutral pH, driedover magnesium sulphate and evaporated. The residue was purified byflash chromatography (heptane/ethyl acetate gradient) to yield6-(tert-butoxycarbonylamino-methyl)-1H-indazole-3-carboxylic acid ethylester as a crystalline white solid, 0.99 g (63%), m/z (ISP): 320.1(M+H).

Step 3. 6-(tert-Butoxycarbonylamino-methyl)-1H-indazole-3-carboxylicacid ethyl ester (0.94 g, 2.9 mmol) was reacted with4-difluoromethoxy-benzyl bromide in analogy to example 42, step 1.6-(tert-Butoxycarbonylamino-methyl)-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylicacid ethyl ester was obtained as a crystalline white solid, 0.74 g(53%), m/z (ISP): 476.3 (M+H).

Step 4.6-(tert-Butoxycarbonylamino-methyl)-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylicacid ethyl ester (0.2 g, 0.4 mmol) was dissolved in a 4N solution of HClin dioxane (2.0 mL) and stirred at room temperature for 30 min. Thevolatiles were evaporated to yield crude6-aminomethyl-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acidethyl ester hydrochloride as a white crystalline solid, 0.17 g (100%),m/z (ISP): 376.1 (M+H).

Step 5. A solution of6-aminomethyl-1-(4-difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acidethyl ester hydrochloride (0.16 g, 0.40 mmol) in dichloromethane (2.0mL) was cooled to 0° C. and treated with triethylamine (0.064 g, 0.63mmol) and methanesulfonyl chloride (0.064 g, 0.44 mmol). The mixture wasstirred at 0° C. for 15 min, then at room temperature for 45 min. Afurther aliquot of triethylamine (0.087 g) was added and the mixturestirred for further 45 min. The mixture was partitioned between ethylacetate and 1N HCl. The organic phase was washed with water and brineuntil neutral pH, then dried over magnesium sulphate and evaporated. Theresidue was crude1-(4-difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylicacid ethyl ester, 0.18 g (96%), m/z (ISP): 454.4 (M+H).

Step 6.1-(4-Difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylicacid ethyl ester (0.18 g, 0.4 mmol) was hydrdolyzed in analogy toexample 33, step 4.1-(4-Difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylicacid was obtained as a crystalline white solid, 0.17 g (100%), m/z(ISP): 426.0 (M+H).

Step 7.1-(4-Difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylicacid (0.08 g, 0.2 mmol) was coupled to 4-(1H-tetrazol-5-yl)-phenylaminehydrochloride in analogy to example 33, step 4.1-(4-Difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide was obtained as a yellowcrystalline solid, 0.053 g (49%), m/z (ISP): 567.2 (M−H).

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Polyvinylpyrrolidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mgPolyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide(yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magesiumstearate and compressed to yield kernels of 120 or350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Aceticacid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of polyethylene glycol400 and water for injection (part). The pH is adjusted to 5.0 by aceticacid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mgMicrocrystalline cellulose (AVICEL PH 102) 1400.0 mg Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives 1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

Unless stated to the contrary, all compounds in the examples wereprepared and characterized as described. All ranges recited hereinencompass all combinations and subcombinations included within thatrange limit. All patents and publications cited herein are herebyincorporated by reference in their entirety.

1. A compound of formula (I):

or a pharmaceutically acceptable salt or ester thereof, wherein: X is—C(O)—NH—, —NH—C(O)—, or —(CR⁷R⁸)_(m)—S—, wherein R⁷ and R⁸independently from each other are selected from the group consisting ofhydrogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, andfluoro-lower-alkoxy; and m is 0 or 1; Y is —(CR⁹R¹⁰)_(n)—, wherein R⁹and R¹⁰ independently from each other are selected from the groupconsisting of hydrogen, lower alkyl, fluoro-lower-alkyl, lower-alkoxy,and fluoro-lower-alkoxy; and n is 0 or 1; R¹, R², R³ and R⁴independently from each other are selected from the group consisting of:(1) hydrogen, (2) halogen, (3) lower-alkyl, (4) fluoro-lower-alkyl, (5)lower-alkoxy, (6) fluoro-lower-alkoxy, (7) carbamoyl, (8)lower-alkyl-NH—C(O)—NH, (9) aryl-lower-alkyl-NH—C(O)—NH, and (10)lower-alkyl-SO₂—NH-lower-alkyl; R⁵ is phenyl or a heteroaryl selectedfrom the group consisting of (a) thiophenyl, (b) pyridinyl, (c) furanyl,and (d) thiazolyl, which phenyl or heteroaryl is optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of: (1) halogen, (2) lower-alkyl, (3) fluoro-lower-alkyl, (4)lower-alkoxy, (5) fluoro-lower-alkoxy, (6) hydroxy, (7) HO—SO₂, (8)NH₂—SO₂, (9) N(H,lower-alkyl)-SO₂, (10) N(lower-alkyl)₂-SO₂, (11)lower-alkyl-SO₂—NH, (12) carboxy, (13) carboxy-lower-alkyl, (14)carboxy-lower-alkoxy, (15) NO₂, (16) CN, (17)NH₂, (18) N(H,lower-alkyl),(19) N(lower-alkyl)₂, (20) NH₂C(O), (21) N(H,lower-alkyl)C(O), (22)N(lower-alkyl)₂C(O), (23) lower-alkyl-C(O)NH, (24) 1H-tetrazol-5-yl and(25) 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; R⁶ is C₂₋₇-alkyl or

wherein: (a) R¹¹ and R¹² independently from each other are selected fromthe group consisting of hydrogen, lower-alkyl, fluoro-lower-alkyl,lower-alkoxy, and fluoro-lower-alkoxy; (b) R¹³, R¹⁴ and R¹⁵independently from each other are selected from the group consisting ofhydrogen, lower-alkyl, halogen, fluoro-lower-alkyl, lower-alkoxy,hydroxy, fluoro-lower-alkoxy, NO₂ or NH₂—C(O); and (c) R¹⁶ is hydrogenor lower-alkoxy; with the proviso that the compound of formula (I) isnot: N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,4-methyl-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,4-nitro-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,4-chloro-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,4-methoxy-N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzamide,N-[1-(phenylmethyl)-1H-indazol-3-yl]-benzenacetamide, orN-(1-ethyl-1H-indazol-3-yl)-benzamide.
 2. A compound of claim 1, whereinX is —C(O)—NH— or —NH—C(O)—.
 3. A compound of claim 1, wherein R¹, R²,R³ and R⁴ independently from each other are selected from the groupconsisting of: hydrogen, halogen, carbamoyl, lower-alkyl-NH—C(O)—NH,aryl-lower-alkyl-NH—C(O)—NH, and lower-alkyl-SO₂—NH-lower-alkyl.
 4. Acompound of claim 1, wherein R¹, R², R³ and R⁴ independently from eachother are hydrogen or halogen.
 5. A compound of claim 1, wherein R¹, ishydrogen.
 6. A compound of claim 1, wherein R² is hydrogen.
 7. Acompound of claim 1, wherein R³ is hydrogen or fluoro.
 8. A compound ofclaim 1, wherein R⁴ is hydrogen.
 9. A compound of claim 1, wherein R⁵ isphenyl or heteroaryl selected from the group consisting of thiophenyl,pyridinyl, furanyl and thiazolyl, which phenyl or heteroaryl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halogen, lower-alkyl, lower-alkoxy,carboxy, carboxy-lower-alkyl, carboxy-lower-alkoxy, 1H-tetrazol-5-yl,and 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl.
 10. A compound of claim 1,wherein R⁵ is phenyl or thiophenyl, which phenyl or thiophenyl isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halogen, lower-alkoxy, carboxy and1H-tetrazol-5-yl.
 11. A compound of 1, wherein R⁵ is 4-carboxy-phenyl,thiophenyl, phenyl, 3-fluoro-phenyl, 3-methoxy-phenyl, or4-(1H-tetrazol-5-yl)-phenyl.
 12. A compound of claim 1, wherein R⁶ is

and R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are as defined in claim
 1. 13. Acompound of claim 1, wherein R⁷ is hydrogen and R⁸ is hydrogen.
 14. Acompound of claim 1, wherein R⁹-R¹² is hydrogen.
 15. A compound of claim1, wherein R¹³, R¹⁴ and R¹⁵ independently from each other are selectedfrom the group consisting of hydrogen, halogen, fluoro-lower-alkyl,fluoro-lower-alkoxy, and NH₂—C(O).
 16. A compound of claim 1, wherein:(a) R¹³ is hydrogen, trifluoromethyl or chloro; and (b) R¹⁴ is hydrogen,difluoromethoxy or NH₂—C(O).
 17. A compound of claim 1, wherein R¹⁵ ishydrogen and R¹⁶ is hydrogen.
 18. A compound of claim 1, wherein m is 1.19. A compound of claim 1, selected from the group consisting of:N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-terephthalamic acid,N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-benzamide,Thiophene-2-carboxylic acid[1-(4-difluoromethoxy-benzyl)-1H-indazol-3-yl]-amide,N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-3-fluoro-benzamide,N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-3-methoxy-benzamide,N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-isonicotinamide,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamicacid,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide,Thiophene-2-carboxylic acid[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-amide; and anypharmaceutically acceptable salt or ester thereof.
 20. A compound ofclaim 1, selected from the group consisting of:N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-isonicotinamide,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-nicotinamide,N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic acid,N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide,N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide,N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide,Thiophene-2-carboxylic acid[1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide, Furan-2-carboxylicacid [1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,N-[1-(4-Difluoromethoxy-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamicacid, and any pharmaceutically acceptable salt or ester thereof.
 21. Acompound of claim 1, selected from the group consisting of:N-[1-(3-Chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-terephthalamic acid,Thiophene-2-carboxylic acid[1-(3-chloro-benzyl)-7-fluoro-1H-indazol-3-yl]-amide,N-[1-(3-Chloro-benzyl)-6-fluoro-1H-indazol-3-yl]-terephthalamic acid,Thiophene-2-carboxylic acid[1-(4-difluoromethoxy-benzyl)-6-fluoro-1H-indazol-3-yl]-amide,Thiophene-2-carboxylic acid (1-benzyl-1H-indazol-3-yl)-amide,1-Ethyl-5-(3-propyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide,1-Ethyl-5-(3-isopropyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide,1-Ethyl-5-(3-phenethyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide,1-Ethyl-5-(3-ethyl-ureido)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide, 1-(4-Nitro-benzyl)-1H-indazole-3-carboxylicacid (pyridin-3-ylmethyl)-amide, and any pharmaceutically acceptablesalt or ester thereof.
 22. A compound of claim 1, selected from thegroup consisting of:1-(4-Difluoromethoxy-benzyl)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide,1-(3-Trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide,4-({[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-methyl)-benzoicacid,(2-{[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-thiazol-4-yl)-aceticacid, 1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide,1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide,(4-{[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carbonyl]-amino}-2-methyl-phenoxy)-aceticacid, 1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazole-3-carboxylicacid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide, and anypharmaceutically acceptable salt or ester thereof.
 23. A compound ofclaim 1, selected from the group consisting of:4-{[5-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carbonyl]-amino}-benzoicacid, 5-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide,5-Fluoro-1-(3-trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide,1-(4-Carbamoyl-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide,1-(4-Carbamoyl-benzyl)-5-fluoro-1H-indazol e-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide,1-(5-Chloro-2-methoxy-benzyl)-5-fluoro-3-[4-(1H-tetrazol-5-yl)-phenylsulfanylmethyl]-1H-indazole,1-(4-Difluoromethoxy-benzyl)-1H-indazole-3,6-dicarboxylic acid 6-amide3-[4-(1H-tetrazol-5-yl)-benzylamide], and1-(4-Difluoromethoxy-benzyl)-6-(methanesulfonylamino-methyl)-1H-indazole-3-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide, and any pharmaceuticallyacceptable salt or ester thereof.
 24. A compound of claim 1, selectedfrom the group consisting of:N-[1-(4-Difluoromethoxy-benzyl)-1H-indazol-3-yl]-terephthalamic acid,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamicacid,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-benzamide,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-fluoro-benzamide,Thiophene-2-carboxylic acid[1-(4-difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,N-[1-(4-Difluoromethoxy-benzyl)-5-fluoro-1H-indazol-3-yl]-3-methoxy-benzamide,N-[1-(3-Chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-terephthalamic acid,Thiophene-2-carboxylic acid[1-(3-chloro-benzyl)-5-fluoro-1H-indazol-3-yl]-amide,1-(3-Trifluoromethyl-benzyl)-1H-indazole-3-carboxylic acid(thiophen-2-ylmethyl)-amide, and1-(4-Carbamoyl-benzyl)-1H-indazole-3-carboxylic acid4-(1H-tetrazol-5-yl)-benzylamide, and any pharmaceutically acceptablesalt or ester thereof.
 25. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.